Benzospiran derivatives

ABSTRACT

This invention relates to novel benzospiran derivatives embraced by the formula ##SPC1## 
     Wherein the sum of A and B is at least the integer 2; A is selected from the group consisting of --(CH 2 ) n  -- wherein n is 1 through 5 and --(C n  H 2n  -- 2  XY)-- wherein X is selected from the group consisting of hydroxy, acetoxy, amino and acetamido and Y is hydrogen, and X when taken together with Y is selected from the group consisting of =O and =CR 3  R 4  wherein R 3  and R 4  are selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; B is absent or --(CH 2 ) n  -- wherein n is 1 through 3; R 1  is selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; R 2  is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, ##EQU1## WHEREIN N IS 2 THROUGH 5 AND Ar is phenyl having zero through three substituents selected from the group consisting of lower alkyl of 1 through 3 carbon atoms, lower alkoxy of 1 through 3 carbon atoms, bromine, chlorine and fluorine; R 1  and R 2  taken together with --N&lt; is a saturated heterocyclic amino radical selected from the group consisting of unsubstituted and substituted pyrrolidino, piperidino, and hexamethylenimino; Z is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, lower alkoxy of 1 through 3 carbon atoms, nitro, amino, monoalkylamino of 1 through 3 carbon atoms, acylamido of 1 through 4 carbon atoms, bromine, chlorine and fluorine; and a pharmacologically acceptable acid addition salt thereof. It also relates to intermediates and processes for the preparation of the aforesaid novel compounds (1) and novel derivatives thereof. The administration to humans and animals of the novel compounds (1) depresses their central nervous systems and lowers their blood pressures.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel organic compounds, particularly novelbenzospiran derivatives embraced by the formula ##SPC2##

Wherein the sum of A and B is at least the integer 2; A is selected fromthe group consisting of --(CH₂)_(n) ⁻ wherein n is 1 through 5 and--(C_(n) H_(2n) --₂ XY)-- wherein X is selected from the groupconsisting of hydroxy, acetoxy, amino and acetamido and Y is hydrogen,and X when taken together with Y is selected from the group consistingof =0 and =CR³ R⁴ wherein R³ and R⁴ are selected from the groupconsisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; B isabsent or --(CH₂)_(n) ⁻ wherein n is 1 through 3; R¹ is selected fromthe group consisting of hydrogen and lower alkyl of 1 through 3 carbonatoms; R² is selected from the group consisting of hydrogen, lower alkylof 1 through 3 carbon atoms, ##EQU2## WHEREIN N IS 2 THROUGH 5 AND Ar isphenyl having zero through three substituents selected from the groupconsisting of lower alkyl of 1 through 3 carbon atoms, lower alkoxy of 1through 3 carbon atoms; bromine, chlorine and fluorine; R¹ and R² takentogether with --N< is a saturated heterocyclic amino radical selectedfrom the group consisting of unsubstituted and substituted pyrrolidino,piperidino, and hexamethylenimino; Z is selected from the groupconsisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, loweralkoxy of 1 through 3 carbon atoms, nitro, amino, monoalkylamino of 1through 3 carbon atoms, acylamido of 1 through 4 carbon atoms, bromine,chlorine and fluorine; and pharmacologically acceptable acid additionsalts thereof.

The preferred compounds of this invention embraced by Formula I,immediately above, are those having the formula ##SPC3##

which are inclusive of those represented by the formulae ##SPC4##

wherein A, B, Ar, n, R¹ and Z have the same meaning as above and R⁵ isselected from the group consisting of hydrogen, hydroxy and methylene;and a pharmacologically acceptable acid addition salt thereof.

Examples of Ar are phenyl, m-chlorophenyl, p-fluorophenyl,m-ethylphenyl, o-methylphenyl, 3,4-dimethoxyphenyl, 2,4-dimethylphenyl,2-bromo-5-ethylphenyl, 2-chloro-3,5-dipropylphenyl and2,4,6-trichlorophenyl. Examples of lower alkyl of 1 through 3 carbonatoms are methyl, ethyl, propyl and isopropyl. Examples of lower alkoxyof 1 through 3 carbon atoms are methoxy, ethoxy, propoxy, andisopropoxy. Examples of unsubstituted and substituted pyrrolidino,piperidino and hexamethylenimino are pyrrolidino, 2-methylpyrrolidino,piperidino, 2-ethylpiperidino, hexamethylenimino,3-methoxyhexamethylenimino and 2-ethyl-4-methylhexamethylenimino.Examples of ##EQU3## is phenyl having from zero through threesubstituents selected from the group consisting of fluorine, chlorine,bromine, lower alkyl of 1 through 3 three carbon atoms and lower alkoxyof 1 through 3 carbon atoms, are: 4-oxo-4-(p-fluorophenyl)-butyl,4-oxo-4-(2-chloro-1-methylphenyl)butyl, 4-oxo-4-phenylbutyl,4-oxo-4-(p-tolyl)butyl, 4-oxo-4-(p-methoxyphenyl)butyl,4-oxo-4-(p-chlorophenyl)butyl, 4-oxo-(2-bromo-4-chlorophenyl)butyl,3-oxo-3-(p-bromophenyl)propyl, 5-oxo-4-(o-ethoxyphenyl)pentyl, and theisomeric forms thereof. Examples of monoalkylamino of 1 through 3 carbonatoms are methylamino, ethylamino, propylamino and isopropylamino.Examples of acylamido of 1 through 4 carbon atoms are formylamido,acetamido, propionamido and isopropionamido.

The novel benzospiran compounds of Formula I exist either in thenon-protonated (free base) form or in the protonated (acid additionsalt) form, depending on the pH of the environment. They form stableprotonates, i.e., acid addition salts, on neutralization of the freebase form with suitable acids, for example, hydrochloric, hydrobromic,sulfuric, phosphoric, nitric, acetic, propionic, palmitic, benzoic,salicylic, hexynoic, phenylbutyric, naphthoic, glycolic, succinic,nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, citric andlactic acids, and the like. Conversely, the free base of the novelcompounds of Formula I can be obtained from a salt (e.g., from thehydrochloride or sulfate salts) by neutralization with a base such assodium hydroxide, extracting with an immiscible solvent, for examplechloroform, drying the extract, for example, with anhydrous sodiumsulfate, and removing the solvent by evaporation.

The novel compounds of generic Formula I, above, include those of threetypes, namely, 3',4'-dihydro-spiro[cyclohexane-1,1'(2'H)-naphthalene]shaving the general structure ##SPC5##

spiro[cyclohexane-1,2'-indan]s of the general structure ##SPC6##

and spiro[cyclohexane-1,2'-tetralin]s of the general structure ##SPC7##

wherein R¹, R² and Z have the same meaning as above and R⁵ is selectedfrom the group consisting of hydrogen, hydroxy and methylene.

The novel compounds of Formula I (a, b and c), above, and intermediatestherefor are prepared in accordance with the procedures of Processes A,B and C, respectively, described below.

Process A

The following sequence of formulae illustratively represents proceduresfor the preparation of compounds of Formula I(a). ##SPC8##

wherein Ar, n and Z have the same meaning as above, R is lower alkyl of1 through 3 carbon atoms, the symbol --N

represents a saturated heterocyclic amino radical selected from thegroup consisting of unsubstituted and substituted pyrrolidino,piperidino and hexamethyleneimino and X is selected from the groupconsisting of chlorine, bromine and an anion of a pharmacologicallyacceptable acid addition salt.

The compounds embraced by Formula I(a) of the flowsheet designatedProcess A, above, are prepared by the procedures indicated therein,employing the methods and reactions described below.

1. The first step of the process comprises reducing a known4-cyano-4-phenylcyclohexanone (a), e.g., with sodium borohydride (in asolvent such as tetrahydrofuran) at low temperature, to yield acorresponding 4-cyano-4-phenylcyclohexanol (b).

2. A thus produced 4-cyano-4-phenylcyclohexanol (b) obtained in step (1)is directly reduced, e.g., with lithium aluminum hydride (in a solventsuch as tetrahydrofuran) at elevated (reflux) temperature, to give acorresponding 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde (c). Thiscompound is also prepared via the tetrahydropyranyl ether of (b).

3. A 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde (c) produced in step(2) is first converted to its corresponding tetrahydropyranyl ether (d)(e.g., by mixing it will dihydropyran in the presence of an acidcatalyst such as p-toluenesulfonic acid in a solvent such as ether),then the formyl function of said ether (d) alkyllated via the Wittigreaction (e.g., by reacting it with a mixture of atrialkylphosphonoacylate, in a solvent such as tetrahydrofuran, andsodium hydride, followed by heating at reflux) to give a correspondingalkyl-4-hydroxy-1-phenylcyclohexaneacrylate tetrahydropyranyl ether (e),followed by hydrolysis of said compound (e); for example, with analkanol (such as methanol) acidified with an acid such as hydrochloricacid, to give a correspondingalkyl-4-hydroxy-1-phenylcyclohexaneacrylate (f).

4. An alkyl- 4-hydroxy-1-phenylcyclohexaneacrylate (f) prepared in step(3) is reduced catalytically (e.g., with hydrogen in the presence ofpalladium on carbon), to give a correspondingalkyl-4-hydroxy-1-phenylcyclohexane-3-propionate (g).

5. An alkyl-4-hydroxy-1-phenylcyclohexane-3-propionate (g) obtained instep (4) is hydrolyzed, e.g., by heating it at reflux with an alkalimetal hydroxide (such as sodium hydroxide) in an alkanol (such asmethanol), to yield a corresponding4-hydroxy-1-phenylcyclohexane-3-propionic acid (h).

6. The next step of the process comprises oxidizing the 4-hydroxylfunction of a 4-hydroxy-1-phenylcyclohexane-3-propionic acid (h)produced in step (5), e.g., with Jones reagent (chromium trioxide --sulfuric acid), preferably at ice bath temperature, to yield acorresponding 4-oxo-1-phenylcyclohexane 3-propionic acid (i).

The compounds embraced by intermediate (i) can also be prepared byanother method, namely, via alkylene ketals, as follows:

1'. A 4-cyano-4-phenylcyclohexanone (a) is ketalized, e.g., by heating(at reflux) in benzene with an alkylene glycol (in the presence of acatalyst such as p-toluenesulfonic acid), to yield a corresponding4-cyano-4-phenylcyclohexanone alkylene ketal (j).

2'. A 4-cyano-4-phenylcyclohexanone alkylene ketal (j) produced in step(1') is converted with about 0.5 mole equivalent of lithium aluminumhydride (in a solvent such as tetrahydrofuran) at room temperature to acorresponding imine, followed by its hydrolysis (e.g., in a solvent suchas tetrahydrofuran with an acid such as hydrochloric acid), to yield acorresponding 4-oxo-1-phenylcyclohexanecarboxaldehyde 4-alkylene ketal(k).

3'. A 4-oxo-1-phenylcyclohexanecarboxaldehyde 4-alkylene ketal (k)produced in step (2') is alkylated via the Wittig reaction (e.g., byreacting it with a mixture of a trialkylphosphonoacetate, in a solventsuch as tetrahydrofuran, and sodium hydride, followed by heating atreflux) to give a corresponding alkyl-4-oxo-1-phenylcyclohexaneacrylatealkylene ketal (l).

4'. An alkyl-4-oxo-1-phenylcyclohexaneacrylate alkylene ketal (l)prepared in step (3') is reduced catalytically (e.g., with hydrogen inthe presence of palladium on carbon), to give a correspondingalkyl-4-oxo-1-phenylcyclohane-3-propionate alkylene ketal (m).

5'. An alkyl-4-oxo-1-phenylcyclohexane-3-propionate alkylene ketal (m)obtained in step (4') is hydrolyzed, e.g., by heating it at reflux withan alkali metal hydroxide (such as sodium hydroxide) in an alkanol (suchas methanol), to give a corresponding4-oxo-1-phenylcyclohexane-3-propionic acid alkylene ketal (n).

6'. In this step, the alkylene ketol protective group of a4-oxo-1-phenylcyclohexane-3-propionic acid alkylene ketal (n) producedin step (5') is removed by employing conventional reagents andprocedures, e.g., by stirring an aforesaid compound with a diluteaqueous acid (e.g., hydrochloric) in acetone at moderate (room)temperature for a long (6 to 60 hour) period, to give a corresponding4-oxo-1-phenylcyclohexane-3-propionic acid (i), also produced by themethod ending with step (6), above.

7. A 4-oxo-1-phenylcyclohexane-3-propionic acid (i) prepared in step (6)or (6') is cyclized, e.g., by allowing it to stand at room temperaturefor from about 15 to about 80 hours with liquid hydrogen fluoride, toyield a correspondingspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione (o).

8. A spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione (o)prepared in step (7) is monoketalized at the non-conjugated leasthindered carbonyl function, e.g., by heating (at reflux) in a solventsuch as benzene with an alkylene glycol (in the presence of a catalystsuch as p-toluenesulfonic acid), to yield a correspondingspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dialkyltrimethylene ketal) (p).

9. A spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dialkyltrimethylene ketal (p) produced in step (8) is reduced atthe 4'-position, e.g., by long (about 12 to about 18 hours) heating (atreflux) with hydrazine hydrate and an alkali metal base such as sodiumhydroxide in a solvent such as an alkylene glycol (e.g., ethyleneglycol) to give a corresponding3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-one,2,2-dialkyltrimethylene ketal (g).

10. In this step, a3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-one,2,2-dialkyltrimethylene ketal (q) prepared in step (9) has its ketalprotective group removed by hydrolysis, e.g., by mixing it with an acid(such as hydrochloric acid) in a solvent (such as acetone) at moderate(room) temperature for from about 2 to about 10 hours, to yield acorresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r).

11. A 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one (r)produced in step (10) has its 4-keto function reduced, e.g., by mixingsaid compound in a solvent such as ethanol with sodium borohydride atmoderate (room) temperature for from about 3 to about 8 hours, toproduce a corresponding3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol (s).

12. Letting stand (preferably at low temperature for from about 3 toabout 14 hours) a mixture of a3',4'-dihydrospiro[cyclohexane-1,1'-(2'H)-naphthalen]-4-ol (s) obtainedin step (11) in an amine base (e.g., pyridine) and a lower alkylsulfonyl halide (such as methanesulfonyl chloride), yields acorresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)naphthalen]-4-ollower alkyl sulfonate (t).

13. A 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol alkylsulfonate (t) resulting from step (12) and sodium azide in a solventsuch as dimethylformamide, on heating (at from about 65° to about 100°C. for from about 4 to about 24 hours), yields a corresponding3',4'-dihydrospiro[cyclohexane 1,1'(2'H)-1,1'(2'H)-naphthalen]-4-ylazide(u).

14. A3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-1,1'(2'H)-naphthalen]-4-ylazide(u) obtained in step (13) on reduction of its azido function, e.g., byreacting said compound with lithium aluminum hydride in a solvent suchas tetrahydrofuran at moderate (room) temperature for from about 3 toabout 10 hours, yields a corresponding3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine [I(a)] inits free base form. On treating an ether extract of a thus producedcompound with an ethereal solution of a suitable (pharmacologicallyacceptable) acid, its acid addition salt form is obtained.

The free base or acid addition salt forms of the3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamines [I(a)]obtained as in step (14), above, are employed as starting materials forproducing a variety of derivatives thereof, for example, in accordancewith the methods described in (a) through (e) that follow.

a. Heating (e.g., under reflux for from about 8 to about 24 hours) a3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine [I(a)]obtained in step (14) with a dihaloalkane, gives a corresponding(1-single ring nitrogen containingheterocyclo)-3',4'-dihydrospiro-(cyclohexane- 1,1'(2'H)-naphthalen)-4-yl[I(a)], which on dissolving in ether and treating with an etherealsolution of an appropriate acid, yields the corresponding acid additionsalt. For example, heating a3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine [I(a)]with 1,5-diiodopentane, 1,4-dibromobutane or 1,6-diiodohexane, yields,respectively a corresponding1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]piperidine[I(a)], a1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl)pyrrolidine[I(a)] or a1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]hexamethyleneimine[I(a)], which can be converted to their acid addition salts in themanner described in the immediately preceding sentence.

b. The production of a compound selected from the group consisting ofthe free bases and acid addition salts of a4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]alkanophenoneof the formula ##SPC9##

wherein Ar, n and Z have the same meaning as above, comprises reacting(in the presence of an alkali metal iodide and an alkali metalcarbonate) a corresponding compound obtained as in step (14) selectedfrom the group consisting of the free bases and acid salts of a compoundof the formula ##SPC10##

wherein Z has the same meaning as above, with a corresponding compoundof the formula ##SPC11##

wherein Ar, R and n have the same meaning as above and X is selectedfrom the group consisting of chlorine and bromine, followed byhydrolyzing (i.e., deketalizing) a thus produced compound, e.g., withaqueous acid in an alkanol.

c. Reacting a3',4'-dihydrospiro[cyclohexane-1,1'-(2'H)-naphthalen]-4-ylamine [I(a)]obtained as in step (14), in an amine base (such as pyridine) in thecold with a lower alkyl haloformate (e.g., ethyl chloroformate,methylbromoformate or propyl chloroformate), yields a correspondinglower alkyl3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate of theformula ##SPC12##

wherein R and Z have the same meaning as above.

d. A lower alkyl3',4'-dihydrospiro[cyclohexane1,1'(2'H)-naphthalene]-4-carbamate I(a),prepared as in (c) immediately above, is reduced, for example, byheating it in a solvent such as tetrahydrofuran [e.g., under reflux forfrom about 8 to about 24 hours] with lithium aluminum hydride, to yielda corresponding3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-loweralkylamine [I(a)], which on dissolving in ether and treating with anethereal solution of an appropriate acid gives a corresponding acidaddition salt thereof.

e. Following the procedure of (b), above, but substituting as startingmaterial the free base or acid addition salt of a3',4'-dihydrospiro[cyclohexane-1,1'-(2'H)-naphthalen]-4-yl-N-loweralkylamine [I(a)], obtained as in (d) immediately above, yields acorresponding 4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-2through 5-yl-N-lower alkylamino]alkanophenone [I(a)], or an acidaddition salt thereof.

Process B

The following sequence of formulae illustratively represents proceduresfor the preparation of compounds of Formulae I(b). ##SPC13##

wherein Ar, n, -N , R, X and Z have the same meaning as in Process A,above.

The compounds embraced by formula I(b) of the flowsheet designatedProcess B, above, are prepared by the procedures indicated therein,employing the methods and reactions described below.

1. The first step of the process comprises reducing an alkyl p-hydroxybenzoate [1] (prepared as in Ann. 141, 247), e.g., by hydrogenating itin the presence of a catalyst (such as 5 percent rhodium/aluminum) in asolvent (such as absolute ethanol) at room temperature, to yield acorresponding alkyl-4-hydroxycyclohexane carboxylate [2].

2. An alkyl-4-hydroxycyclohexane carboxylate [2] obtained in step (1) isoxidized at the 4-position, e.g., in acetone with Jones reagent as lowtemperature (at from about 5° to about 20° C.) to give a corresponding4-carboalkoxy-1-cyclohexanone [3].

3. A 4-carboalkoxy-1-cyclohexanone [3] prepared in step (2) is ketalizedat the 4-position, e.g., by heating (at reflux) in benzene with analkylene glycol (in the presence of a catalyst such as p-toluenesulfonicacid) for from about 4 to about 8 hours, to yield a corresponding4-carboalkoxy-1-cyclohexanone alkylene ketal [4].

4. A 4-carboalkoxy-1-cyclohexanone alkylene ketal [4] obtained in step(3) on reaction with lithium diisopropyl amide (prepared by adding butyllithium in a solvent such as pentane to diisopropylamine in a solventsuch as tetrahydrofuran at low temperature) followed by addition of abenzyl halide (such as α-bromotoluene, α-chloro-p-xylene,α-bromo-m-xylene, m-methoxybenzyl chloride, and the like), yields acorresponding 4-benzyl (or substitutedbenzyl)-4-carboalkoxy-1-cyclohexane alkylene ketal [5].

5. A 4-benzyl (or substituted benzyl)-4-carboalkoxy-1-cyclohexanealkylene ketal [5] obtained in step (4) is saponified, e.g., by heating(at reflux for from about 10 to about 24 hours) in a solvent such asethylene glycol with an alkali metal hydroxide (such as potassiumhydroxide), to give a corresponding 4-benzyl (or substitutedbenzyl)-4-carboxy-1-cyclohexanone alkylene ketal [6].

6. A 4-benzyl (or substituted benzyl)-4-carboxy-1-cyclohexanone alkyleneketal [6] prepared in step (5) is deketalized, e.g., by stirring it witha dilute aqueous acid (e.g., hydrochloric acid) in acetone at moderate(room) temperature for from about 6 to about 60 hours, to give acorresponding 1-benzyl (or substitutedbenzyl)-4-cyclohexanone-1-carboxylic acid [7].

7. Reacting a 1-benzyl (or substitutedbenzyl)-4-cyclohexanone-1-carboxylic acid [7] obtained in step (6) withhydrogen fluoride at room temperature (or with phosphorus pentachlorideat reflux temperature, followed by treatment with stannic chloride),gives a corresponding unsubstituted or substitutedspiro(cyclohexane-1,2'-indan)-1'4-dione [8].

8. An unsubstituted or substitutedspiro(cyclohexane-1,2'-indan)-1'4-dione [8] obtained in step (7) isketalized at the 4-position, e.g., by heating (at reflux) in benzenewith an alkylene glycol (in the presence of a catalyst such asp-toluenesulfonic acid) for from about 3 to 7 hours, to yield acorresponding unsubstituted or substitutedspiro(cyclohexane-1,2'-indan)-1',4-dione 4-alkylene ketal [9].

9. A spiro(cyclohexane-1,2'-indan)-1'4-dione 4-alkylene ketal [9]prepared in step (8) on being subjected to Wolff-Kischner reduction,namely, by heating it (at reflux) with hydrazine hydrate and an alkalimetal hydroxide (such as potassium hydroxide) in a solvent such asethylene glycol for from about 8 to about 12 hours, gives acorresponding spiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [10].

10. A spiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [10] obtainedin step (9) is deketalized, e.g., by stirring it with a dilute aqueousacid (such as hydrochloric acid) in acetone for from about 3 to about 8hours, to give a corresponding spiro(cyclohexane-1,2'-indan)-4-one [11].

11. A spiro(cyclohexane-1,2'-indan)-4-one [11] obtained in step (10), onheating at reflux for from about 4 to about 8 hours with an acidaddition salt of hydroxylamine and an alkali metal hydroxide such assodium hydroxide, yields a correspondingspiro(cyclohexane-1,2'-indan)-4-one oxime [12].

12. A spiro(cyclohexane-1,2'-indan)-4-one oxime [12] prepared in step(11), on standing in a solvent such as tetrahydrofuran with an anhydrideof a hydrocarbon carboxylic acid in the presence of an esterificationcatalyst (e.g., pyridine) at moderate (room) temperature for from about4 to about 8 hours, yields a correspondingspiro(cyclohexane-1,2'-indan)-4-one oxime acylate [13].

13. A spiro(cyclohexane-1,2'-indan)-4-one oxime acylate [13] produced instep (12), on reducing its oxime function, e.g., by reacting saidcompound with diborane in a solvent such as tetrahydrofuran (preferablyat low temperature), yields a correspondingspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] in its free base form,which on extracting with ether and treating said extract with anethereal solution of a suitable (pharmacologically acceptable) acid,gives the corresponding acid addition salt form.

The compounds embraced by the spiro(cyclohexane-1,2'-indan)-4-amines andtheir acid addition salts [I(b)], immediately above, can be prepared byanother method, as follows:

11'. A spiro(cyclohexane-1,2'-indan)-4-one [11] obtained in step (10)has its 4-keto function reduced, e.g., by mixing said compound inethanol with sodium borohydride at moderate (room) temperature for fromabout 3 to about 8 hours, to produce a correspondingspiro(cyclohexane-1,2'-indan)-4-ol [14].

12'. Letting stand (preferably at low temperature for from about 3 toabout 18 hours) a mixture of a spiro(cyclohexane-1,2'-indan)-4-ol [14]obtained in step (11') in an amine base (e.g., pyridine) and a loweralkyl sulfonyl halide (such as methanesulfonyl chloride), yields acorresponding spiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonate[15].

13'. A spiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonate [15]obtained in step (12') and sodium azide in a solvent such asdimethylformamide, on heating (at from 65° to about 100° C. for fromabout 4 to about 20 hours), yields a correspondingspiro(cyclohexane-1,2'-indan)-4-ylazide [16]; on reduction of the azidofunction of a thus produced compound [16], e.g., by reacting saidcompound with lithium aluminum hydride in a solvent such astetrahydrofuran at moderate (room) temperature for from about 3 to about10 hours, yields a corresponding spiro(cyclohexane-1,2'-indan)-4-amine[I(b)] in its free base form, which on extracting with ether andtreating said extract with an ethereal solution of a suitable acid,gives the corresponding acid addition salt form.

The free base or acid addition salt forms of thespiro(cyclohexane-1,2'-indan)-4-amines [I(b)] obtained as in step (13)or (13'), above, are employed as starting materials for preparing avariety of derivatives thereof, for example, in accordance with themethods set forth in (a) through (e) that follow.

a. Heating (e.g., under reflux for from about 8 to about 24 hours) aspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] obtained in step (13) or(13') with a dihaloalkane, yields a corresponding (1-single ringnitrogen containing heterocyclo)-spiro(cyclohexane-1,2'-indan)-4-yl[I(b)], which on dissolving in ether and treating with an etherealsolution of an appropriate acid, gives the corresponding acid additionsalt thereof. For example, heating aspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] with 1,5-diiodopentane,1,4-dibromobutane or 1,6-diiodohexane, yields, respectively, an acidaddition salt of a corresponding1-[spiro(cyclohexane-1,2'-indane)-4-yl]piperidine [I(b)], a1-[spiro(cyclohexane-1,2'-indane)-4-yl]pyrrolidine [I(b)] or a1-spiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimine [I(b)], whichcan be converted to their acid addition salts in the manner described inthe immediately preceding sentence.

b. The production of a compound selected from the group consisting ofthe free bases and acid addition salts of a4-[[spiro[cyclohexane-1,2'-indan]-4-yl]amino]alkanophenone of theformula ##SPC14##

wherein Ar, n and Z have the same meaning as above, comprises reacting(in the presence of an alkali metal iodide and an alkali metalcarbonate) a corresponding compound obtained in step (13) or (13')selected from the group consisting of the free bases or acid additionsalts of a compound of the formula ##SPC15##

wherein Z has the same meaning as above, with a corresponding compoundof the formula ##SPC16##

wherein Ar, R and n have the same meaning as above and X is selectedfrom the group consisting of chlorine and bromine, followed byhydrolyzing (i.e., deketalizing) a thus produced compound, e.g., withaqueous acid in an alkanol.

c. Reacting a spiro(cyclohexane-1,2'-indan)-4-amine [I(b)] obtained instep (13) or (13'), haloformate (e.g., ethyl chloroformate, methylbromoformate or propyl chloroformate) yields a corresponding lower alkylspiro(cyclohexane-1,2'-indane)-4-carbamate having the formula ##SPC17##

wherein R and Z have the same meaning as above.

d. A lower alkyl spiro(cyclohexane-1,2'-indane)4-carbamate [I(b)],prepared as in (c) immediately above, is reduced, e.g., by heating it(under reflux) in a solvent such as tetrahydrofuran (for from about 8 toabout 24 hours) with lithium aluminum hydride, to yield a correspondingspiro(cyclohexane-1,2'-indane)-4-yl-N-methylamine [I(b)], which ondissolving in ether and treating with an ethereal solution of anappropriate acid gives a corresponding acid addition salt thereof.

e. Following the procedure of (b), above, but substituting the free baseor acid addition salt of aspiro(cyclohexane-1,2'-indane)-4-yl-N-methylamine [I(b)] obtained as in(d) immediately above as starting material, yields a corresponding[spiro[cyclohexane-1,2'-indan]-2 through 5-yl-N-loweralkylamino]alkanophenone [I(b)], or an acid addition salt thereof.

The unsubstituted and substitutedspiro(cyclohexane-1,2'-indan)-1'4-dione alkylene ketals [9] prepared instep (8) of Process B can be employed as starting materials forproducing a variety of 1'-hydroxyspiro(cyclohexane-1,2'-indan) compounds[I(b)] by the procedures that follow.

1. A spiro(cyclohexane-1,2'-indan)-1'4-dione alkylene ketal [9] has its1'-keto function reduced, e.g., by reacting said compound with lithiumaluminum hydride in a solvent such as tetrahydrofuran at moderate (room)temperature for from about 3 to about 10 hours, yields a corresponding1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [17].

2. A 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [17]produced in step (1) has its ketal protective group removed byhydrolysis, e.g., by allowing said compound to stand for from about 4 toabout 20 hours with an acid (such as hydrochloric acid) in a solventsuch as acetone) at room temperature, to yield a corresponding1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one [18].

3. A 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one [18] prepared in step(2), on standing at room temperature for from about 5 to about 10 hoursin a solvent such as tetrahydrofuran with an anhydride of a hydrocarboncarboxylic acid in the presence of an esterification catalyst (e.g.,pyridine), yields a corresponding1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-one [19].

4. A 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-one [19] produced in step(3) has its 4-keto function reduced, e.g., by stirring said compound (ina solvent such as isopropanol) with sodium borohydride at moderate(room) temperature for from about 1/2 to about 4 hours, to give acorresponding 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol [20].

5. Letting stand (preferably in the cold for from about 4 to about 20hours) a mixture of a 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol [20]obtained in step (4) in an amine base (e.g., pyridine and a lower alkylsulfonyl halide (e.g., methanesulfonyl chloride), yield a corresponding1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonate [21].

6. A 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonate[21] obtained in step (5) and sodium azide in a solvent such asdimethylformamide, on heating (at from about 65° to about 100° C. forfrom about 4 to about 20 hours), yields a corresponding1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ylazide [22], which onreduction, e.g., by reaction with lithium aluminum hydride in a solventsuch as tetrahydrofuran at room temperature for from 8 to about 16hours, yields a corresponding1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] in its free baseform, which on extracting with ether and treating the extract with anethereal solution of a suitable acid, (e.g., hydrochloric), gives thecorresponding acid addition salt form.

The free base or acid addition salt forms of the1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amines [I(b)] obtained in step(6) immediately above, are employed as starting materials for preparinga variety of derivatives thereof, for example, in accordance with themethods set forth in (a) through (e) that follow.

a. Heating (e.g., under reflux for from about 8 to about 24 hours) a1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] obtained in step(6) with a dihaloalkane, yields a corresponding (1-single ring nitrogencontaining heterocyclo)-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-yl[I(b)], which on dissolving in ether and treating with an appropriateacid, gives the corresponding acid addition salt thereof. For example,heating a 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] with1,5-diiodopentane, 1,4-dibromobutane or 1,6-diiodohexane, yields,respectively, a corresponding1'-hydroxy-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidine [I(b)], a1'-hydroxy-1-[spiro(cyclohexane-1,2'-indane)-4-yl]pyrrolidine [I(b)] ora 1'-hydroxy-1-[spiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimine[I(b)], which are converted to their acid addition salts in the mannerdescribed in the immediately preceding sentence.

b. The production of a compound selected from the group consisting ofthe free bases and acid addition salts of a4-[(1'-hydrospiro[cyclohexane-1,2'-indan]-4-yl)amino]alkanophenone[I(b)] comprises: reacting (in the presence of an alkali metal iodideand an alkali metal carbonate) a corresponding1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] obtained in step(6) with a corresponding 2,2-dialkyl-1,3-propanediol ketal of aω-haloalkanophenyl ketone, followed by hydrolyzing a thus producedcompound.

c. Reacting a 1'-hydroxy-4-[[spiro[cyclohexane-1,2'-4-amine [I(b)]obtained in step (6) in pyridine in the cold with a lower alkylhaloformate, yields a corresponding loweralkyl-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-carbamate [I(b)].

d. A lower alkyl-1'-hydroxy-spiro(cyclohexane-1,2'-indane)-4-carbamate[I(b)], prepared as in (c) immediately above, is reduced by heating withlithium aluminum hydride, to yield a corresponding1'-hydroxy-spiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamine [I(b)],which on dissolving in ether and treating with an ethereal solution ofan appropriate acid give a corresponding acid addition salt thereof.

e. Following the procedure of (b), above, but substituting the free baseor acid addition salt of a1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkyl-amine [I(b)]obtained as in (d) immediately above as starting material, yields acorresponding 4-[1'-hydroxyspiro[cyclohexane-1,2'-indan]-2 through5-yl-N-lower alkylamino]-alkanophenone [I(b)], or an acid addition saltthereof.

The unsubstituted and substituted1'-hydroxy-spiro(cyclohexane-1,2'-indan)-4-one alkylene ketals [17]prepared in step (1) of the process set forth immediately above, can beused as starting materials for producing a variety1'-acetamido-spiro(cyclohexane-1,2'-indan) compounds by the proceduresthat follow.

1. A 1'-hydroxy-spiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [17]in a solvent such as tetrahydrofuran is treated in the cold with butyllithium in a solvent such as pentane and a lower alkyl sulfonyl halide(such as methanesulfonyl chloride) in a solvent (e.g., tetrahydrofuran),to give a corresponding 1'-halospiro(cyclohexan-1,2'-indan)-4-onealkylene ketal [23].

2. A 1'-halospiro(cyclohexan-1,2'-indan)-4-one alkylene ketal [23]produced in step (1) is heated with sodium azide in a solvent such asdimethylformamide at from about 80° to about 100° C. for from about 15to about 24 hours and the resulting azido intermediate recovered byconventional procedures and then reduced (e.g., with lithium aluminumhydride in a solvent such as tetrahydrofuran), to give a corresponding1'-aminospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [24].

3. A 1'-aminospiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [24]prepared in step (2) is acylated, e.g., by treating it with an anhydrideof a hydrocarbon carboxylic acid (such as acetic anhydride) in thepresence of a catalyst (such as pyridine), to give a corresponding1'-acylamidospiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [25].

4. A 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [25]produced in step (3), is hydrolyzed, e.g., by standing at roomtemperature for from about 5 to about 20 hours with an acid such ashydrochloric acid in a solvent such as acetone, to give a corresponding1'-acylamidospiro(cyclohexane-1,2'-indan)-4-one [26].

5. A 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-one [26] obtained instep (4) has its 4-keto function reduced, e.g., by reacting saidcompound with sodium borohydride in a solvent such as isopropanol atmoderate (room) temperature for from about 3 to about 10 hours, to givea mixture of 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ols [27], whichare separated into their two isomers by conventional procedures, e.g.,chromatography or fractional crystallization.

6. Letting either of the isomers of the1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ols [27] obtained in step(5) stand for from about 3 to about 10 hours in an amine base (e.g.,piperidine) with a lower alkyl sulfonyl halide (e.g., methanesulfonylchloride, yields a corresponding1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonate[28].

7. A 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonate[28] obtained in step (6) and sodium azide in a solvent such asdimethylformamide, on heating (at from about 65° to about 100° C. forfrom about 4 to about 20 hours), yields a corresponding1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ylazide, which on reduction,e.g., by reaction with lithium aluminum hydride in a solvent such astetrahydrofuran at room temperature for from about 8 to about 16 hours,yields a corresponding 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amine[I(b)] in its free base form, which on extracting with ether andtreating said extract with an ethereal solution of a suitable acid(e.g., hydrochloric) gives the corresponding acid addition salt form.

The free base or acid addition salt forms of the1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines [I(b)] obtained instep (7) immediately above, are employed as starting materials forpreparing a variety of derivatives thereof, in the same manner asdescribed above using the corresponding1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amines [I(b)] as startingcompounds set forth in (a) through (e) following step (6) of thesynthesis of said 1'-hydroxyspiro compounds [I(b)]. By utilizing theaforesaid procedures, compounds such as the following are obtained:

a. 1'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidines[I(b)], 1'-acylamido-1-[spiro(cyclohexane)-1,2'-indan)-4-yl]pyrrolidines[I(b)] and1'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimines[I(b)];

b.4-[(1'-acylamidospiro[cyclohexane-1,2'-indan]-4-yl)aminoalkanophenones[I(b)] and acid addition salts thereof;

c. lower alkyl-1'-acylamidospiro(cyclohexane-1,2'-indane)-4-carbamates[I(b)];

d. 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamines[I(b)]; and

e. 4-[1'-acylamidospiro(cyclohexane-1,2'-indan)-4-yl-N-loweralkylamino]alkanophenones [I(b)], and acid addition salts thereof.

The free base or acid addition salt of a5'-acylamidospiro(cyclohexane-1,2'-indan)-4-amine [I(b)], also named anN-[4-aminospiro[cyclohexane-1,2'-indan]-5'-yl]acylamide [I(b)], isprepared from a spiro(cyclohexane-1,2'-indan)-4-one [11] startingcompound, by employing the procedures that follow.

1. A spiro(cyclohexane-1,2'-indan)-4-one [11] [prepared as above in step(10) of the first process for producing the compounds of Process B] inthe cold (at about 0° C.) in trifluoroacetic acid, has nitric acid addedthereto and the low temperature maintained for from about 1 to about 4hours, to yield a corresponding5'-nitrospiro(cyclohexane-1,2'-indan)-4-one [29] .

2. A 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one [29] produced in step(1) is catalytically reduced (e.g., with hydrogen in the presence ofpalladium on carbon, in a solvent such as ethyl acetate), to give acorresponding 5'-aminospiro(cyclohexane-1,2'-indan)-4-one [30] .

3. A 5'-aminospiro(cyclohexane-1,2'-indan)-4-one [30] prepared in step(2) is treated in the cold (at about 0° C.) with an amine base such aspyridine and the anhydride of a hydrocarbon carboxylic acid (e.g.,acetic anhydride) for from about 3 to about 8 hours, to give acorresponding 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-one [31] .

4. A 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-one [31] prepared instep (3) has its 4-keto function reduced, e.g., by reacting saidcompound with sodium borohydride in a solvent such as isopropanol atmoderate (room) temperature for from about 3 to about 10 hours, to givea corresponding 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol [32] .

Using a thus produced 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol[32] as starting material and employing the procedures described insteps (6) and (7) and (a) through (e), above, for preparing thecorresponding 1'acylamido compounds, yields 5'-acylamido counterpartssuch as

6. 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonates[33] ;

7. 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ylazides [34] and5'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines [I(b)] (as free baseor acid addition salt);

a. 5'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidines[I(b)], 5'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]pyrrolidines[I(b)] and5'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimines[I(b)];

b.4-[[5'-acylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]alkanophenones[I(b)] and acid addition salts thereof;

c. lower alkyl-5'-acylamidospiro(cyclohexane-1,2'-indan)-4-carbamates[I(b)];

d. 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamines[I(b)]; and

e. 4-[5'-acylamidospiro[cyclohexane-1,2'-indan)-4-yl-N-loweralkylamino]alkanophenones [I(b)], and acid addition salts thereof.

The unsubstituted or substituted spiro(cyclohexane-1,2'-indan)-1'4-dionealkylene ketals [9][prepared as in step (8) of the first process forproducing the compounds of Process B] can be employed as startingmaterials for preparing a variety of1'-exomethylenespiro(cyclohexane-1,2'-indan) compounds by the proceduresthat follow.

1. A spiro(cyclohexane-1,2'-indan)-1'4-dione-4-alkylene ketal (9) in asolvent such as tetrahydrofuran, on addition to a methyl magnesiumhalide (such as methyl magnesium bromide) in a solvent such as ether,after standing at moderate (room) temperature for from about 6 to about24 hours, gives a corresponding1'-hydroxy-1'-methyl-spiro(cyclohexane-1,2'-indan)-4-one alkylene ketal[40] .

2. A 1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one alkyleneketal [40] produced in step (1), on stirring with an acid (such ashydrochloric) in a solvent (such as acetone) at room temperature forfrom about 4 to about 20 hours, yields a corresponding1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one [41 .

3. A 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one [41] preparedin step (2) has its 4-keto function reduced, e.g., by stirring saidcompound (in a solvent such as isopropanol with sodium borohydride atmoderate (room) temperature for from about 2 to about 10 hours, to givea corresponding 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42] .

4. Letting stand (preferably in the cold for from about 4 to about 20hours) a mixture of a 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42] obtained in step (3) in an amine base (such as pyridine) and alower alkyl sulfonyl halide (such as methanesulfonyl chloride), yields acorresponding 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol loweralkyl sulfonate [43] .

5. A 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol loweralkylsulfonate [43] obtained in step (4) and sodium azide in a solventsuch as dimethylformamide, on heating at from about 65° to about 100°C.for from about 4 to about 20 hours, gives a corresponding1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ylazide [44], which onreduction, e.g., with lithium aluminum hydride in a solvent such astetrahydrofuran at room temperature for from about 4 to about 16 hours,yields a corresponding1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine [I(b)] in its freebase form, which on extracting with ether and treating said extract withan ethereal solution of a suitable acid (e.g., hydrochloric), gives thecorresponding acid addition salt form.

The free base or acid addition salt forms of 1'-exomethylenespiro(cyclohexane-1,2'-indan)-4-amines [I(b)] obtained in step(5) immediately above, are employed as starting materials for preparinga variety of derivatives thereof, in the same manner as described aboveusing the corresponding 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amines[I(b)] as starting compounds set forth in (a) through (e) following step(6) of the synthesis of said 1'-hydroxyspiro compounds [I(b)]. Byfollowing the aforesaid procedures, there are obtained 1'-exo-methylenecounterparts such as

a. 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-piperidines [I(b)],1'-exo-methylenespiro(cyclohexane-1,2'-indan)pyrrolidines [I(b) ] and1'-exo-methylenespiro(cyclohexane-1,2'-indan)hexamethyleneimines [I(b)];

b. alkanophenones of1'-exo-methylenespiro(cyclohexane-1,2'-indan-4-amine [I(b)], also names4-[[1'-methylenespiro(cyclohexan-1,2'-indan)-4-yl]amino]alkanophenones[I(b)], and acid additon salts thereof;

c. lower alkyl1'-exo-methylenespiro(cyclohexane-1,2'-indane)-4-carbamates [I(b)];

d. 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl-N-loweralkylamines [I(b)]; and

e. 4-[1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl-N-loweralkylamino]alkanophenones [I(b)] and acid addition salts thereof.

Process C

The following sequence of formulae illustratively represents proceduresfor the preparation of compounds of Formula I(c). ##SPC18##

wherein Ar, n, --N , R, X and Z have the same meaning as in Process A,above.

The compounds embraced by Formula I(c) of the flow-sheet designatedProcess C, above, are prepared by the procedures indicated therein,employing the methods and reactions described below.

1. The first step of the process comprises reducing a 4-benzyl (orsubstituted benzyl)-4-carboalkoxy-1-cyclohexanone alkylene ketal [5][prepared as above in step (4) of the first process for producing thecompounds of Process B], for example, by reacting it in a solvent suchas tetrahydrofuran with lithium aluminum hydride and heating thereaction mixture (at reflux) for from about 3 to about 8 hours, to givea corresponding 4-benzyl (or substitutedbenzyl)-4-hydroxymethylcyclohexan-1-one alkylene ketal (1).

2. A 4-benzyl (or substituted benzyl)-4-hydroxymethyl-cyclohexan-1-onealkylene ketal (1) obtained in step (1) in an amine base (such aspyridine) on standing in the cold with a lower alkyl sulfonyl halide(such as methanesulfonyl chloride), yields a corresponding 4-benzyl (orsubstituted benzyl)-4-hydroxymethylcyclohexan-1-one, alkylene ketal,lower alkyl sulfonate (2).

3. A 4-benzyl (or substituted benzyl)-4-hydroxymethylcyclohexan-1-one,alkylene ketal lower alkyl sulfonate (2) prepared in step (2) on heatingfor from about 10 to about 18 hours at from about 100° to about 165° C.with potassium cyanide in a solvent such as hexamethylphosphoramide,yields a corresponding 4-benzyl-4-cyanomethylcyclohexan-1-one alkyleneketal (3).

4. A thus produced 4-benzyl-4-cyanomethylcyclohexan-1-one alkylene ketal(3) obtained in step (3) on saponification, e.g., by heating it with analkali metal hydroxide (such as potassium hydroxide) in a solvent suchas an alkalene glycol (e.g., ethylene glycol) for from about 8 to about18 hours, gives a corresponding 4-benzylcyclohexan-4-acetic acid-1-onealkylene ketal (4).

5. A 4-benzylcyclohexane-4-acetic acid-1-one alkylene ketal (4) preparedin step (4) is deketalized, e.g., by stirring it with a dilute aqueousacid (e.g., hydrochloric) in acetone at moderate (room) temperature forfrom about 36 to about 72 hours, to give a corresponding4-benzylcyclohexan-4-acetic acid-1-one (5).

6. A 4-benzylcyclohexane-4-acetic acid-1-one (5) prepared in step (5) iscyclized, e.g., by allowing it to stand at moderate (room) temperaturefor from about 15 to about 80 hours with liquid hydrogen fluoride, toyield a corresponding3',4'-dihydroxpiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione (6).

7. A 3', 4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4', 4-dione(6) obtained in step (6) is monoketalized at the non-conjugated leasthindered carbonyl function, e.g., by heating (at reflux) in a solventsuch as benzene with an alkylene glycol (in the presence of a catalystsuch as p-toluenesulfonic acid), to yield a corresponding 3', 4',-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4 -dione,4-(ethylene ketal) (7).

8. A 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4 -dione,4-(ethylene ketal) (7) prepared in step (7) is reduced at the1'-position, e.g., by heating (at reflux) for from about 1/2 to about 3hours with hydrazine hydrate and a base (e.g., potassium hydroxide) in asolvent such as an alkylene glycol (e.g., ethylene glycol), to give acorresponding 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethylene ketal(8).

9. In this step, a3',4'4'-dihydrospiro[cyclohexane-1,2'-(1'H)-naphthalen]-4-one, ethyleneketal (8) obtained in step (8) has its ketal protective group removed byhydrolysis, e.g., by heating it (at reflux) for from about 8 to about 20hours with an acid (such as hydrochloric) in a solvent (such asacetone), to yield a corresponding3',4'4'-dihydrospiro[cyclohexane-1,2'(1'H)-napththalen]-4-one (9).

10. A 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-oneproduced, e.g., by mixing said compound in a solvent such as isopropanolwith sodium borohydride at moderate (room) temperature, to give acorresponding 3' ,4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol(10).

11. A 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-olobtained in step (10) on standing in the cold (at about 0° C.) for fromabout 3 to about 6 hours in an amine base (e.g., pyridine) with a loweralkyl sulfonyl halide (e.g., methanesulfonyl chloride), gives acorresponding 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ollower alkyl sulfonate (11).

12. A 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol loweralkyl sulfonate prepared in step (11) and sodium azide in a solvent suchas dimethylformamide, on heating (at from about 65° to about 100° C. forfrom about 4 to about 20 hours); yields a corresponding3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylazide, which onreaction with lithium aluminum hydride in a solvent such astetrahydrofuran at moderate (room) temperature for from about3 to about10 hours, yields a corresponding 3',4'-dihydrospiro(cyclohexane-1,2'(1'H)-naphthalen)-4-ylamine [I(c)] in itsfree base form. On treating an ether extract of a thus produced compoundwith an ethereal solution of a suitable (pharmacologically acceptable)acid, its acid addition salt form is obtained.

The free base or acid addition salt forms of the 3',4'-dihydrospirol[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamines [I(c)]obtained as in step (12), above, are employed as starting materials forproducing a variety of derivatives thereof, for example, in accordancewith the methods described in (a) through (e) that follow.

a. Heating (e.g., under reflux for from about 8 to about 24 hours) a3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)]obtained in step (12) with a dihaloalkane, gives a corresponding(1-single ring nitrogen containing heterocyclo)-3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl [I(c)], which ondissolving in ether and treating with an ethereal solution of anappropriate acid, yields the corresponding acid addition salt. Forexample, heating a 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c) ] with1,5-diiodopentane, 1,4-dibromobutane or 1,6-diiododhexane, yields,respectively, a corresponding 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine [I(c)],a 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]pyrrolidine [I(c)]or a 1-[3',4'-dihydrospiro(cyclohexane-1,2'(1'H)-naphthalen)-4-yl[hexamethyleneimine[I(c)], which can be converted to their acid addition salts in themanner described in the immediately preceding sentence.

b. The production of a compound selected from the group consisting ofthe free bases and acid addition salts of a4-[(3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl)amino]alkanophenoneof the formula ##SPC19##

wherein Ar, n and Z have the same meaning as above, comprises reacting(in the presence of an alkali metal iodide and an alkali metalcarbonate) a corresponding compound obtained as in step (12) selectedfrom the group consisting of the free bases and acid addition salts of acompound of the formula ##SPC20##

wherein Z has the same meaning as above, with the corresponding compoundof the formula ##SPC21##

wherein Ar, R and n have the same meaning as above and X is selectedfrom the group consisting of chlorine and bromine, followed byhydrolyzing (i.e., deketalizing) a thus produced compound, e.g., withaqueous acid in an alkanol.

c. Reacting a3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)]obtained as in step (12), in pyridine in the cold with a lower alkylhaloformate (e.g., ethyl chloroformate, methyl bromoformate, propylchloroformate or isopropyl bromoformate), yields a corresponding loweralkyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamateof the formula ##SPC22##

wherein R and Z have the same meaning as above.

d. A lower alkyl3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate[I(c)], prepared as in (c) immediately above, is reduced, e.g., byheating it in a solvent such as tetrahydrofuran (under reflux for fromabout 6 to about 24 hours) with lithium aluminum hydride, to yield acorresponding3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamine[I(c)], which on dissolving in ether and treating with an etherealsolution of an appropriate acid gives a corresponding acid addition saltthereof.

e. Following the procedure of (b), above, but substituting as startingmaterial the free base or acid addition salt of a3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino[I(c)], obtained as in (d) immediately above, yields a corresponding4-[(3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-2 through5-yl-N-methylamino]alkanophenone [I(c)], or an acid addition saltthereof.

All of the compounds included within Formula I (a, b and c) of theflow-sheets, above, can be isolated from their respective reactionmixtures by conventional means, for example, when a water-misciblesolvent is used, by pouring the reaction mixture into water randseparating the resulting precipitate by filtration or by extraction withwater-immiscible solvents. Additional purification of the products canbe accomplished by conventional means, for example, by elutionchromatography from an adsorbent column with a suitable solvent such asacetone, ethyl acetate, ether, methylene chloride and Skellysolve B(hexanes), mixtures and combinations of these solvents; also by gradientelution chromatography from an adsorbent column with a suitable mixtureof solvents, such as, methylene chloride-Skellysolve B,acetone-Skellysolve B, and the like.

The free bases and acid addition salts of the novel compounds of FormulaI are useful as central nervous system (CNS) depressants whenadministered to humans and animals. They possess tranquilizing activityand are consequently useful in humans for controlling anxiety andschizophrenia; in animals the aforesaid compounds are useful for theircalming effects and can be given to reduce aggressive behavior. Thesecompounds have been shown to possess CNS depressing activity (especiallytranquilizing activity) via the loss of righting reflex, traction,chimney, dish and pedestal tests carried out in the manner described byBoissier et al. in Medicina Experimentalis 4, 145 (1961).

Tranquilizing effects of compounds of this invention are shown by thefollowing tests in mice:

Chimney test: [Med. Exp. 4, 145 (1961)]: The test determines the abilityof mice to back up and out of a verticle glass cylinder within 30seconds. At the effective dosage, 50 percent of the mice failed doingit.

Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partiallyembedded in wood shavings), climb out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes indicatestranquilization. ED₅₀ equals the dose of test compound at which 50percent of the mice remain in the dish.

Pedestal test: The untreated mouse leaves a standard pedestal in lessthan a minute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than 1 minute.

Nicotine antagonism test: Mice in a group of 6 are injected with thetest compound. Thirty minutes later the mice including control(untreated) mice are injected with nicotine salicylate (2 mg./kg.). Thecontrol mice show overstimulation, i.e., (1) running convulsionsfollowed by (2) tonic extensor fits; followed by (3) death.

The following compounds typical of this invention have (byintraperitoneal injection) ED₅₀ as shown in the table below.

    ______________________________________                                                         ED.sub.50 (in mg./kg.)                                       COMPOUND           Ch      D       P     Ni                                   ______________________________________                                        4'-fluoro-4-[(3',4'-dihydro-                                                  spiro[cyclohexane-1,1'(2'H)-                                                  naphthalen]-4-yl)amino]butyro-                                                phenone hydrochloride [I(a)]                                                                     25      10      16    5                                    4'-fluoro-4-[methyl(spiro-                                                    [cyclohexane-1,2'-indan)-4-                                                   yl)amino] butyrophenone hydro-                                                chloride [I(b)]    16      3.6      9    4                                    4'-fluoro-4-[(3',4'-dihydro-                                                  spiro[cyclohexane-1,2'(1'H)-                                                  naphthalen]-4-yl)amino]butyro-                                                phenone hydrochloride [I(c)]                                                                     9.9     9.9     12.5  7                                    ______________________________________                                         Ch = chimney test                                                             D = dish test                                                                 P = pedestal test                                                             Ni = nicotine antagonism (3) test                                        

As tranquilizers, the compounds of Formula I (a, b and c) and theirpharmacologically acceptable acid addition salts can be prepared andadministered to humans, mammals, birds and animals in a wide variety oforal or parenteral dosage forms, singly or in admixture with othercoacting compounds, in doses of from about 10 mg. to about 100 mg./kg.,depending on the severity of the condition being treated and therecipient's response to the medication.

The free bases and pharmacologically acceptable acid addition salts ofthe compounds of Formula I (a, b and c) are also useful in loweringblood pressure when administered to humans and animals. This activitymakes them useful in the treatment of essential hypertension. Thesecompounds have been shown to possess hypotensive activity when tested inthe manner described by Weeks and Jones, in Proc. Soc. Exp. Biol. andMed. 104, 646 (1960). The following compounds typical of this inventionhave (by oral administration to rats) MED₁₀₀ (minimal effective dose) asshown in the table below.

    ______________________________________                                        COMPOUND             MED.sub.100 (in mg./kg.)                                 ______________________________________                                        4'-fluoro-4-[(spiro[cyclohexane                                               1,2'-indan]-4-yl)amino]butyro-                                                phenone hydrochloride [I(b)]                                                                       50                                                       4'-fluoro-4-[[1'-hydroxyspiro-                                                [cyclohexane-1,2'-indan]-4-yl]-                                               amino]butyrophenone hydrochloride                                             [I(b)]               50                                                       ______________________________________                                    

As hypotensives, the compounds of Formula I (a, b and c) and theirpharmacologically acceptable acid addition salts can be prepared andadministered to humans, mammals, birds and animals in a wide variety oforal or parenteral dosage forms, singly or in admixture with othercoacting compounds in doses of from about 10 mg. to about 100 mg./kg.,depending on the severity of the condition being treated and therecipient's response to the medication.

The compounds of Formula I (a, b and c) (used as tranquilizers and/orhypotensives) can be administered with a pharmaceutical carrier whichcan be solid material or a liquid in which the compound is dissolved,dispersed or suspended. The solid compositions can take the form oftablets, powders, capsules, pills or the like, preferably in unit dosageforms for simple administration or precise dosages. The liquidcompositions can take the form of solutions, emulsions, suspensions,syrups, or elixirs.

DETAILED DESCRIPTION

The following examples are illustrative of the manner of making andusing the invention and set forth the best mode comtemplated by theinventor of carrying out his invention, but are not to be construed aslimiting the scope thereof, as obvious modifications and equivalentswill be apparent to those skilled in the art, and the invention istherefore to be limited only by the scope of the appended claims.

EXAMPLE 1A

4-Cyano-4-phenylcyclohexano(b)

To an ice and methanol cooled solution of 4 g. (0.0205 M) of4-cyano-4-phenylcyclohexanone (a) (prepared as in J. Chem. Soc. 1959,1446) in 150 ml. of tetrahydrofuran, a suspension of 1 g. of sodiumborohydride in 50 ml. of tetrahydrofuran is added in 5 ml. portions inthe course of about 10 minutes. The mixture is stirred for about 30minutes and allowed to stand in the cold for about 18 hours. The bulk ofthe solvent is removed under vacuum and the residue treated with water.The precipitate is extracted with ether and the organic fraction washedsuccessively with 2.5 N hydrochloric acid solution, saturated aqueoussodium bicarbonate, water and brine and then evaporated to dryness. Theresidue is recrystallized with benzene to give 1.81 g. (43.8% yield) of4-cyano-4-phenylcyclohexanol (b) melting at 103° to 111° C.

Anal. Calcd. for C₁₃ H₁₅ NO: C, 77.58; H, 7.51; N, 6.96

Found: C, 77.98; H, 7.34; N, 6.58.

Following the procedure of Example 1A but substituting other4-cyano-4-phenylcyclohexanones (a) as starting materials, such as

1. 4-cyano-4-(4-bromophenyl)cyclohexanone(a),

2. 4-cyano-4-(3-fluorophenyl)cyclohexanone(a),

3. 4-cyano-4-(3-methylphenyl)cyclohexanone(a),

4. 4-cyano-4-(2-propylphenyl)cyclohexanone(a),

5. 4-cyano-4-(4-ethoxyphenyl)cyclohexanone(a),

6. 4-cyano-4-(3-aminophenyl)cyclohexanone(a),

7. 4-cyano-4-(4-methylaminophenyl)cyclohexanone(a),

8. 4-cyano-4-(5-ethylaminophenyl)cyclohexanone(a),

9. 4-cyano-4-(2-aceylamidophenyl)cyclohexanone(a), and the like,

yields, respectively,

1. 4-cyano-4-(4-bromophenyl)cyclohexanol(b),

2. 4-cyano-4-(3-fluorophenyl)cyclohexanol(b),

3. 4-cyano-4-(3-methylphenyl)cyclohexanol(b),

4. 4-cyano-4-(2-propylphenyl)cyclohexanol(b),

5. 4-cyano-4-(4-ethoxyphenyl)cyclohexanol(b),

6. 4-cyano-4-(3-aminophenyl)cyclohexanol(b),

7. 4-cyano-4-(4-methylaminophenyl)cyclohexanol(b),

8. 4-cyano-4-(5-ethylaminophenyl)cyclohexanol(b),

9. 4-cyano-4-(2-acetylamidophenyl)cyclohexanol(b), and the like.

EXAMPLE 2A

4-Hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde(c)

A solution of 2 g. (0.01 M) of 2 g. of 4-cyano-4-phenylcyclohexanol(b)(obtained as in Example 1A) in tetrahydrofuran is added to a suspensionof 0.52 g. (0.015 M) of lithium aluminum hydride in 10 ml. oftetrahydrofuran. The mixture is stirred at room temperature for about 15minutes, at reflux for about 1 hours, and then cooled in an ice bath. Toit is added successively 0.52 ml. of water, 0.52 ml. of 15% aqueoussodium hydroxide solution and 1.56 ml. of water. The precipitatedinorganic gel is collected on a filter, washed twice with ether and thecombined filtrates evaporated to dryness. The residue is treated with 20ml. of 1:1 acetic acid:water and 2 drops of concentrated sulfuric acidand heated on a steam bath for about 30 minutes. The mixture is cooledto room temperature, extracted thoroughly with methylene chloride, thecombined extracts washed successively with water, saturated aqueoussodium bicarbonate solution and brine and then evaporated to dryness.The residual product, 1.37 g. (66% yield) of4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde(c) has a melting point of74° to 76° C.

Anal. Calcd. for C₁₃ H₁₆ O₂ : C, 76.44; H, 7.90. l.

Found: C, 76.06; H, 7.84.

Following the procedure of Example 2A but substituting other4-cyano-4-phenylcyclohexanols(b) as starting materials, such as

1. 4-cyano-4-(5-chlorophenyl)cyclohexanol(b),

2. 4-cyano-4-(4-ethylphenyl)cyclohexanol(b),

3. 4-cyano-4-(3-propoxyphenyl)cyclohexanol(b),

4. 4-cyano-4-(5-isopropylaminophenyl)cyclohexanol(b),

5. 4-cyano-4-(4-propionylamidophenyl)cyclohexanol(b), and the like,

yields, respectively,

1. 4-hydroxy-1-(5-chlorophenyl)-1-cyclohexanecarboxaldehyde(c),

2. 4-hydroxy-1-(4-ethylphenyl)-1-cyclohexanecarboxaldehyde(c),

3. 4-hydroxy-1-(3-propoxyphenyl)-1-cyclohexanecarboxaldehyde(c),

4. 4-hydroxy-1-(5-isopropylaminophenyl)-1-cyclohexanecarboxaldehyde(c),

5. 4-hydroxy-1-(4-propionylamidophenyl-1-cyclohexanecarboxaldehyde(c),

and the like.

EXAMPLE 3A

Ethyl-4-hydroxy-1-phenylcyclohexaneacrylate(f)

1. To a partial solution of 3.51 g. (0.017 M) of4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde(c) (obtained as inExample 2A) in 35 ml. of ether, 2 g. of dihydropyan and 0.11 g. of p-toluenesulfonic acid is added. After stirring for a short time at roomtemperature, complete solution is attained. The reaction mixture afterstanding at room temperature for about 4 hours is washed first withsaturated aqueous sodium bicarbonate solution then with brine andevaporated to dryness. The residue is recrystallized once from petroleumether to give 4.53 g. of 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehydepyranyl ether (d), having a melting point of 43.5° to 54° C.

2. A solution of 3.52 g. (0.158M) of triethyl phosphonacetate in 45 ml.of tetrahydrofuran is prepared and 0.67 g. of 56% sodium hydride added.The mixture is stirred at room temperature for about 30 minutes and asolution of (0.158M) of the4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde pyranyl ether (d)[prepared as in (1), above], in 45 ml. of tetrahydrofuran added.Following about 4 hours of heating at reflux and about 15 hours ofstanding at room temperature, most of the solvent is removed undervacuum and the residue taken up in ether and water. The organic layer iswashed with water and brine and then evaporated to dryness to givemethyl-4-hydroxy-1-phenylcyclohexaneacrylate tetrahydropyranyl ether(e).

3. A solution of the methyl-4-hydroxy-1-phenylcyclohexaneacrylatetetrahydropyranyl ether (e) [prepared as in (2), above,] in 75 ml. ofmethanol and 7.5 ml. of 2.5 N hydrochloric acid is stirred at roomtemperature for about 1 hour and then most of the methanol removed undervacuum. The residue is dissolved in ether and water and the organiclayer washed successively with water, saturated aqueous sodiumbicarbonate solution and brine and then evaporated to dryness. Theresidue is chromatographed on a column of 500 g. of silica gel (silicicacid) with elution first by 5.5 l. of methylene chloride, then 20% ethylacetate:methylene chloride. The more polar fractions found similar bythin layer chromatography (TLC) are combined to yield 3.5 g. (80% yield)of ethyl-4-hydroxy-1-phenylcyclohexaneacrylate(f) as a gum.

Following the procedure of Example 3A but substituting other4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehydes(c) as startingmaterials, such as

1. 4-hydroxy-1-(3-bromophenyl)-1-cyclohexanecarboxaldehyde(c),

2. 4-hydroxy-1-(4-propylphenyl)-1-cyclohexanecarboxaldehyde(c),

3. 4-hydroxy-1-(5-ethoxyphenyl)-1-cyclohexanecarboxaldehyde(c),

4. 4-hydroxy-1-(3-methylaminophenyl)-1-cyclohexanecarboxaldehyde(c),

5. 4-hydroxy-1-(2-formylamidophenyl-1-cyclohexanecarboxaldehyde(c), andthe like,

yields, respectively,

1. ethyl-4-hydroxy-1-(3-bromophenyl)cyclohexaneacrylate(f),

2. ethyl-4-hydroxy-1-(4-propylphenyl)cyclohexaneacrylate(f),

3. ethyl-4-hydroxy-1-(5-ethoxyphenyl)cyclohexaneacrylate(f),

4. ethyl-4-hydroxy-1-(3-methylaminophenyl)cyclohexaneacrylate(f),

5. ethyl-4-hydroxy-1-(2-formylamidophenyl)cyclohexaneacrylate(f), andthe like.

EXAMPLE 4A

Ethyl-4-hydroxy-1-phenylcyclohexane-3-propionate(g)

A mixture of 3.5 g. (0.0128 M) of ethyl-4-hydroxy-1-phenylcyclohexaneacrylate(f) (prepared in Example 3A), 150 ml. ofethyl acetate and 0.4 g. of palladium on carbon catalyst is hydrogenateduntil the theoretical amount of hydrogen is consumed. The catalyst iscollected on a filter and the filtrate evaporated to dryness to give3.36 g. (95% yield) ofethyl-4-hydroxy-1-phenylcyclohexane-3-propionate(g) as a gum.

Following the procedure of Example 4A but substituting otheralkyl-4-hydroxy-1-phenylcyclohexaneacrylates(f) as starting materials,such as

1. methyl-4-hydroxy-1-(2-chlorophenyl)cyclohexaneacrylate(f),

2. propyl-4-hydroxy-1-(3-methoxyphenyl)cyclohexaneacrylate(f),

3. methyl-4-hydroxy-1-(5-ethylaminophenyl)cyclohexaneacrylate(f),

4. ethyl-4-hydroxy-1-(4-acetylamidophenyl)cyclohexaneacrylate(f), andthe like,

yields, respectively,

1. methyl-4-hydroxy-1-(2-chlorophenyl)cyclohexane-3-propionate(g),

2. propyl-4-hydroxy-1-(3-methoxyphenyl)cyclohexane-3-propionate(g),

3. methyl-4-hydroxy-1-(5-ethylaminophenyl)cyclohexane-3-propionate(g),

4. ethyl-4-hydroxy-1-(4-acetylamidophenyl)cyclohexane-3-propionate(g),and the like.

EXAMPLE 5A

4-Hydroxy-1-phenylcyclohexane-3-propionic acid (h)

A solution of 0.68 g. (0.0025 M) ofethyl-4-hydroxy-1-phencyclohexane-3-propionate(g) (obtained in Example4A) and 1 ml. of 50% sodium hydroxide in 10 ml. of methanol is heated atreflux for about 20 hours. Most of the solvent is removed under vacuumand the residue dissolved in water. The aqueous solution is washed withether and made acidic with concentrated hydrochloric acid. A solidprecipitate is collected on a filter and recrystallized from benzene togive 0.44 g. (71% yield) of 4-hydroxy-1-phenylcyclohexane-3-propionicacid (h) having a melting point of 153.5° to 155° C.

Anal. Calcd. for C₁₅ H₂₀ O: C, 72.55; H, 8.12.

Found: C, 72.47; H, 8.05.

Following the procedure of Example 5A but substituting otheralkyl-4-hydroxy-1-phenylcyclohexane-3-propionates (g) as startingmaterials, such as

1. methyl-4-hydroxy-1-(3-fluorophenyl)cyclohexane-3-propionate(g),

2. isopropyl-4-hydroxy-1-(4-ethoxyphenylcyclohexane-3-propionate(g),

3. ethyl-4-hydroxy-1-(5-ethylaminophenyl)cyclohexane-3-propionate(g),

4. propyl-4-hydroxy-1-(4-acetylamidophenyl)cyclohexane-3-propionate(g),and the like,

yields, respectively,

1. 4-hydroxy-1-(3-fluorophenyl)cyclohexane-3-propionic acid(h),

2. 4-hydroxy-1-(4-ethoxyphenyl)cyclohexane-3-propionic acid(h),

3. 4-hydroxy-1-(5-ethylaminophenyl)cyclohexane-3-propionic acid(h),

4. 4-hydroxy-1-(4-acetylamidophenyl)cyclohexane-3-propionic acid(h), andthe like.

EXAMPLE 6A

4-Oxo-1-phenylcyclohexane-3-propionic acid(i)

To a mechanically stirred, ice cooled partial solution of 2.36 g.(0.0095 M) of 4-hydroxy-1-phenylcyclohexane-3-propionic acid(h)(prepared as in Example 5A) in acetone, 5 ml. of Jones reagent (chromiumtrioxide-sulfuric acid) is added in the course of about 5 minutes. Mostof the solvent is removed under vacuum and the residue dissolved inether and water. The organic layer is washed with water and brine,evaporated to dryness and the residue recrystallized from methylenechloride: Skellysolve B to give 2.13 g. (91.2% yield) of4-oxo-1-phenylcyclohexane-3-propionic acid(i) having a melting point of139° to 140.5° C.

Anal. Calcd. for C₁₅ H₁₈ O₃ : C, 73.14; H, 7.37.

Found: C, 72.49; H, 7.27.

Following the procedure of Example 6A but substituting other4-hydroxy-1-phenylcyclohexane-3-propionic acids(h) as starting materals,such as

1. 4-hydroxy-1-(3-bromophenyl) cyclohexane-3-propionic acid(h),

2. 4-hydroxy-1-(3-ethylphenyl)cyclohexane-3-propionic acid(h),

3. 4-hydroxy-1-(5-methylaminophenyl)cyclohexane-3-propionic acid(h), andthe like, yields, respectively,

1. 4-oxo-1-(2-bromophenyl)cyclohexane-3-propionic acid(i),

2. 4-oxo-1-(3-ethylphenyl)cyclohexane-3-propionic acid(i),

3. 4-oxo-1-(5-methylaminophenyl)cyclohexane-3-propionic acid(i), and thelike.

EXAMPLE 7A

4-Cyano-4-phenylcyclohexanone, ethylene ketal(j)

A mixture of 10 g. (0.05 M) of 4-cyano-4-cyano-4-phenylcyclohexanone(a),2.85 ml. [3.16 g. (0.51M)] of ethylene glycol and 0.12 g. ofp-toluenesulfonic acid in 90 ml. of benzene is heated at reflux under aDean-Stark trap for about 6 hours. The solution is allowed to cool andthen washed successively with sodium bicarbonate solution, water andbrine. The organic layer is evaporated to dryness and the residuerecrystallized from cyclohexane to give 11.27 g. (92.7% yield) of4-cyano-4-phenylcyclohexanone, ethylene ketal(j), having a melting pointof 120° to 122.5° C.

Anal. Calcd. for C₁₅ H₁₇ NO₂ : C, 74.05; H, 7.04; N, 5.76

Found: C, 74.10; H, 6.98; N, 5.77.

Following the procedure of Example 7A but substituting other4-cyano-4-phenylcyclohexanones(a) as starting materials, such as

1. 4-cyano-4-(4-chlorophenyl)cyclohexanone(a),

2. 4-cyano-4-(4-methoxyphenyl)cylohexanone(a),

3. 4-cyano-4-(3-ethylaminophenyl)cyclohexanone(a),

4. 4-cyano-4-(2-propionylamidophenyl)cyclohexanone(a), and the like,

yields, respectively,

1. 4-cyano-4-(4-chlorophenyl)cyclohexanone, ethylene ketal(j),

2. 4-cyano-4-(4-methoxyphenyl)cyclohexanone, ethylene ketal(j),

3. 4-cyano-4-(3-ethylaminophenyl)cyclohexanone, ethylene ketal (j),

4. 4-cyano-4-(2-propionylamidophenyl)cyclohexanone, ethylene ketal(j),and the like.

EXAMPLE 8A

4-Oxo-1-phenylcyclohexanecarboxaldehyde, 4-ethylene ketal(k)

To a suspension of 0.16 g. (0.0014 M) of lithium aluminum hydride in 10ml. of tetrahydrofuran, 2 g. (0.0082 M) of 4-cyano-4-phenylcyclohexanoneethylene ketal(j) (prepared as in Example 7A) in 100 ml. oftetrahydrofuran is added in the course of about 15 minutes. The mixtureis stirred at room temperature for about 1.75 hours and then cooled inan ice bath, and then 0.16 ml. of water, 0.16 ml. of 15% aqueous sodiumhydroxide solution and 0.48 ml. of water added successively, Theinorganic gel is collected on a filter, rinsed with ether and thecombined filtrates evaporated to dryness. The residue in 30 ml. oftetrahydrofuran and 3 ml. of 2.5 N hydrochloric acid is stirred at roomtemperature for about 15 minutes, treated with 1 g. of sodiumbicarbonate and then evaporated to dryness under vacuum. Ether is addedto the residue, the organic portion separated and evaporated to dryness.The residue is chromatographed on silica gel, eluted with 1% ethylacetate: methylene chloride and the more polar crystalline fractionscombined to yield 0.87 g. (86.4 % of theoretical) of4-oxo-1-phenylcyclohexanecarboxaldehyde, 4-ethylene ketal(k), having amelting point of 56° to 64° C. and nuclear magnetic resonance (NMR) andinfrared (IR) spectra in agreement with the expected structure of thecompound.

Following the procedure of Example 8A but substituting other4-cyano-4-phenylcyclohexane ethylene ketals(j) as starting materials,such as

1. 4-cyano-4-(3-fluorophenyl)cyclohexanone, ethylene ketal(j),

2. 4-cyano-4-(2-ethylphenyl)cyclohexanone, ethylene ketal(j),

3. 4-cyano-4-(4-propylaminophenylcyclohexanone, ethylene ketal(j),

4. 4-cyano-4-(5-acetylamidophenyl)cyclohexanone, ethylene ketal(j), andthe like,

yields, respectively,

1. 4-oxo-1-(3-fluorophenyl)cyclohexanecarboxaldehyde, ethylene ketal(k),

2. 4-oxo-1-(2-ethylphenyl)cyclohexanecarboxaldehyde, ethylene ketal(k),

3. 4-oxo-1-(4-propylaminophenyl)cyclohexanecarboxaldehyde, ethyleneketal(k),

4. 4-oxo-1-(5-acetylamidophenyl)cyclohexanecarboxaldehyde, ethyleneketal(k), and the like.

EXAMPLE 9A

Ethyl -4-oxo-1-phenylcyclohexaneacrylate, ethylene ketal(l)

To a solution of 4.74 g. (0.021 M) of triethyl phosphonoacetate in 60ml. of tetrahydrofuran, 0.89 g. of 57% sodium hydride is added.Following about 10 minutes of stirring at room temperature a solution of5.2 g (0.021 M) of 4-oxo-1-phenylcyclohexanecarboxaldehyde 4-ethyleneketal(k) (prepared as in Example 8A) in 60 ml. of tetrahydrofuran isadded. The solution is stirred at reflux for about 4 hours and at roomtemperature for about 18 hours. Most of the solvent is removed undervacuum, and the residue dissolved in ether and water. The organic layeris washed with water and brine and then evaporated to dryness. Theresidue is chromatographed over a column of 700 ml. of silica gel andeluted, first, with 1,600 ml. of Skellysolve B, then with 4 l. of 5%acetone: Skellysolve B. The ultraviolet absorbing fractions found to bealike by TLC are combined to give 6.38 g. (96% yield) ofethyl-4-oxo-1-phenylcyclohexaneacrylate ethylene ketal(l.) as a gum.

Following the procedure of Example 9A but substituting other4-oxo-1-phenylcyclohexanecarboxaldehyde 4-ethylene ketals(k) as startingmaterials, such as

1. 4-oxo-1-(2-bromophenyl)cyclohexanecarboxaldehyde, ethylene ketal(k),

2. 4-oxo-1-(3-ethoxyphenyl)cyclohexanecarboxaldehyde, ethylene ketal(k),and the like, yields, respectively,

1. ethyl-4-oxo-1-(2-bromophenyl)cyclohexaneacrylate, ethylene ketal(1),

2. ethyl-4-oxo-1-(3-ethoxyphenyl)cyclohexaneacrylate, ethylene ketal(l),and the like.

EXAMPLE 10A

Ethyl-4-oxo-1-phenylcyclohexane-3-propionate, ethylene ketal(m)

A mixture of 6.38 g. (0.0202 M) ofethyl-4-oxo-1-phenylcyclohexaneacrylate ethylene ketal(l) (obtained inExample 9A), 0.63 g. of 10% palladium on carbon catalyst and 150 ml. ofethyl acetate is shaken under an atomsphere of hydrogen until thetheoretical amount is consumed. The catalyst is collected on a filterand the filtrate evaporated to dryness to give 6.38 g. (about 100% oftheoretical yield) of ethyl-4-oxo-1-phenylcyclohexane-3-propionate,ethylene ketal(m) as a crude oil.

Following the procedure of Example 10A but substituting otheralkyl-4-oxo-1-phenylcyclohexaneacrylate ethylene ketals(m) as startingmaterials, such as

1. ethyl-4-oxo-1-(3-methylphenyl)cyclohexaneacrylate, ethylene ketal(l),and the like,

yields,

1. ethyl-4-oxo-1-(3-methylphenyl)cyclohexane-3-propionate, ethyleneketal(m), and the like.

EXAMPLE 11A

4-Oxo-1-phenylcyclohexane-3-propionic acid, ethylene ketal(n)

A solution of 6.38 g. (0.020 M) ofethyl-4-oxo-1-phenylcyclohexane-3-propionate ethylene ketal(m) (obtainedin Example 10A) and 8 ml. of 50% sodium hydroxide solution in 80 ml. ofmethanol is heated at reflux for about 20 hours. Most of the methanol isremoved under vacuum, water added to the residue and the latter washedwith ether. The aqueous layer is then made strongly acidic and thematerial that precipitates is extracted with ether. The combined etherextracts are washed with brine and evaporated to dryness to give4-oxo-1-phenylcyclohexane-3-propionic acid, ethylene ketal(n).

Following the procedure of Example 11A but substituting otheralkyl-4-oxo-1-phenylcyclohexane-3-propionate ethylene ketals(m) asstarting materials, such as

1. propyl- 4-oxo-1-(5-ethoxyphenyl)cyclohexane-3-propionate, ethyleneketal(m),

2. methyl-4-oxo-1-(3-acetylamidophenylcyclohexane- 3-propionate,ethylene ketal(m), and the like,

yields, respectively,

1. 4-oxo-1-(5-ethoxyphenyl)cyclohexane-3-propionic acid, ethyleneketal(n),

2. 4-oxo-1-(3-acetylamidophenyl)cyclohexane-3-propionic acid, ethyleneketal(n), and the like.

EXAMPLE 12A

4-Oxo-1-phenylcyclohexane-3-propionic acid(i)

The 4-oxo-1-phenylcyclohexane-3-propionic acid ethylene ketal(n)obtained in Example 11A is dissolved in 50 ml. of acetone and 5 ml. of2.5 N hydrochloric acid and allowed to stand at room temperature forabout 48 hours. The solution is evaporated to near dryness under vacuumand the residue dissolved in water and ether. The organic layer iswashed with water and brine and evaporated to dryness. The residue isrecrystallized from methylene chloride: Skellysolve B to give 1.7 g.(34.5% yield of 4-oxo-1-phenylcyclohexane-3-propionic acid(i) having amelting point of 143° to 144.5° C. This compound is identical to thecompound prepared in Example 6A.

Anal. Calcd. for C₁₅ H₁₈ O₃ : C, 73.15; H, 7.37

Found: C, 73.04; H, 7.40.

Following the procedure of Example 12A but substituting other4-oxo-1-phenylcyclohexane-3-propionic acid alkylene ketals(n) asstarting materials, such as

1. 4-oxo-1-(3-chlorophenyl)cyclohexane-3-propionic acid, ethyleneketal(n),

2. 4-oxo-1-(4-isopropylphenyl)cyclohexane-3-propionic acid, ethyleneketal(n),

3. 4-oxo-1-(5-methylaminophenyl)cyclohexane-3-propionic acid, ethyleneketal(n), and the like,

yields, respectively,

1. 4-oxo-1-(3-chlorophenyl)cyclohexane-3-propionic acid(i),

2. 4-oxo-1-(4-isopropylphenyl)cyclohexane-3-propionic acid(i),

3. 4-oxo-1-(5-methylaminophenyl)cyclohexane-3-propionic acid(i), and thelike.

EXAMPLE 13A

Spiro [cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)dione(o)

To 5 g. (0.0203 M) of 4-oxo-1-phenylcyclohexane-3-propionic acid(i)(prepared as in Examples 6A or 12A), 5 ml. of hydrogen fluoride isdistilled and the solution allowed to stand at room temperature forabout 20 hours. The residue is dissolved in ether, washed successivelywith water, saturated aqueous sodium bicarbonate solution and brine andthen evaporated to dryness. The residue is recrystallized from ether togive 0.13 g. (28% of theoretical yield) ofspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o) having amelting point of 145.5° to 148° C.

Calcd. for C₁₅ H₁₆ O₂ : C, 78.23; H, 7.88

Found: C, 78.39; H, 7.18

Following the procedure of Example 13A but substituting other4-oxo-1-phenylcyclohexane-3-propionic acids(i) as starting materials,such as

1. 4-oxo-1-(3-propylphenyl)cyclohexane-3-propionic acid(i),

2. 4-oxo-1-(4-ethoxyphenyl)cyclohexane-3-propionic acid(i),

3. 4-oxo-1-(2-ethylaminophenyl)cyclohexane-3-propionic acid(i),

4. 4-oxo-1-(3-acetylamidophenyl)cyclohexane-3-propionic acid(i), and thelike,

yields, respectively,

1. 6'-propylspiro[cyclohexane-1,1'(2'H)naphthalene]-4,4'(3'H)-dione(o),

2. 7'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o),

3.5'-ethylaminospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o),

4.6'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o),and the like.

EXAMPLE 14A

Spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dimethyltrimethylene ketal)(p)

A solution of 3.19 g. (0.014 M) ofspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o) (prepared asin Example 13A), 1.45 g. (0.014 M) of 2,2-dimethylpropanediol and 0.06g. of p-toluenesulfonic acid in 57 ml. of benzene is heated under aDean-Stark trap for about 5.5 hours. The solution is washed withsaturated aqueous sodium bicarbonate and brine and then evaporated todryness. The residue is chromatographed over a column of 400 ml. ofFlorisil (activated magnesium silicate) and eluted with 7.5% ethylacetate; Skellysolve B. The crystalline fractions are combined to yield3.29 g. (75% of theoretical) ofspiro[cyclohexane-1,1'(2'H)-naphthalene]4,4'(3'H)-dione,4-(2,2-dimethyltrimethylene ketal) (p) having a melting point of 136° to138° C.

Anal. Calcd. for C₂₀ H₂₆ O₃ : C, 76.40; H, 8.34

Found: C, 76.49; H, 8.38.

Following the procedure of Example 14A but substituting otherspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'-(3'H)-diones(o) asstarting materials, such as

1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o),

2. 6'-methylspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o),and the like,

yields, respectively,

1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dimethyltrimethylene ketal)(p),

2. 6'-methylspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dimethyltrimethylene ketal)(p), and the like.

EXAMPLE 15A

3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one,2,2-dimethyltrimethylene ketal(q)

A solution of 3.63 g. (0.0115 M) ofspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dimethyltrimethylene ketal(p) (prepared as in Example 14A), 1.54ml. of hydrazine hydrate and 2.23 g. of potassium hydroxide in 28 ml. ofethylene glycol is heated to reflux. Distillate is collected until thepot temperature rises to 200° C. and refluxing is continued for about 18hours. The mixture is poured into water and a precipitated material isextracted with ether. The combined extracts are washed with water andbrine and then evaporated to dryness. The residue is recrystallized frompetroleum ether to give 2.39 g. (69.5% yield) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-one,2,2-dimethyltrimethylene ketal(q) having a melting point of 109° to 111°C.

Anal. Calcd. for C₂₀ H₂₈ O₂ : C, 79.95; H, 9.39

Found: C, 79.95; H, 9.51.

Following the procedure of Example 15A but substituting other3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dimethyltrimethylene ketals) (p) as starting materials, such as

1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dimethyltrimethylene ketal)(p),

2. 6'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione,4-(2,2-dimethyltrimethylene ketal)(p), and the like, yields,respectively,

1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one,2,2-dimethyltrimethylene ketal(q),

2. 6'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one,2,2-dimethyltrimethylene ketal(q), and the like.

EXAMPLE 16A

3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r)

A mixture of 2.39 g. (0.008 M) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one,2,2-dimethyltrimethylene ketal(q) and 2.4 ml. of 2.5 N hydrochloric acidin 24 ml. of acetone is stirred at room temperature for about 6 hours.To the reaction mixture, 15 ml. of water is added and most of theacetone removed under vacuum. Ether is added to the residue, the organiclayer washed successively with water, saturated aqueous sodiumbicarbonate solution and brine and then evaporated to dryness. Theresidue is recrystallized from petroleum ether to give 1.19 g. (70%yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r)having a melting point of 115° to 120° C.

Following the procedure of Example 16A but substituting other3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one,2,2-dimethyltriethylene ketals(q) as starting materials, such as

1. 2'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one,2,2-dimethyltrimethylene ketal(q),

2. 3'-methoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one,2,2-dimethyltrimethylene ketal(q),

3. 4'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one,2,2-dimethyltrimethylene ketal(q), and the like,

yields, respectively,

1. 2'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r),

2. 3'-methoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r),

3. 4'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r), andthe like.

EXAMPLE 17A

3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s)

To a partial solution of 5.10 g. (0.038 M) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen-4-one(r) (preparedas in Example 16A) in 105 ml. of 95% ethanol, 2.59 g. of sodiumborohydride is added and the mixture stirred at room temperature forabout 4 hours. Most of the solvent is removed under vacuum and wateradded to the residue. The material that precipitates is extracted withether and the combined extracts washed with water and brine andevaporated to dryness. The residue is recrystallized once fromSkellysolve B and then chromatographed over a column containing 500 ml.of silica gel with elution by 10% acetone:Skellysolve B. On the basis ofTLC the less polar fractions are combined and recrystallized frombenzene:cyclohexane to give a small amount of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s), having amelting point of 144.5° to 146° C., and an NMR spectrum suggesting thatthe compound has the hydroxy substituent in the axial position.

Anal. Calcd. for C₁₅ H₂₀ O: C, 83.28; H, 9.32

Found: C, 83.53; H, 9.61.

On the basis of melting point the more polar fractions are combined andrecrystallized from Skellysolve B to give 3.89 g. (75.6% yield) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s) having amelting point of 80° to 83° C., and an NMR spectrum suggesting that thecompound has the hydroxy substituent in the equatorial position.

Anal. Calcd. for C₁₅ H₂₀ O: C, 83.28; H, 9.32

Found: C, 83.47; H, 9.55.

Following the procedure of Example 17A but substituting other3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ones(r) asstarting materials, such as

1. 5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r),

2. 6'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r), and thelike,

yields, respectively,

1. trans and cis5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s),

2. trans and cis6'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s), and the like.

EXAMPLLE 18A

3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol, methanesulfonate(t)

To an ice-cooled solution of 3.89 g. (0.018 M) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4ol (obtained inExample 17A) in 40 ml. of pyridine, 4 ml. of methane sulfonyl chlorideis added. The mixture is allowed to stand in the cold for about 6 hoursand then diluted with water. The material that precipitates is extractedwith ether and the combined extracts washed successively with ice cold2.5 N hydrochloric acid, water, saturated aqueous sodium bicarbonatesolution and brine and then evaporated to dryness. The residue isrecrystallized from cyclohexane to give 5 g. (94.3% yield) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methanesulfonate(t), having a melting point of 118° to 120° C.

Anal. Calcd. for C₁₆ H₂₂ O₃ S: C, 65.27; H, 7.53; S, 10.89

Found: C, 65.17; H, 7.61; S, 10.70

Following the procedure of Example 18A but substituting other3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ols(s) asstarting materials, such as

1. 6'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s),

2. 8'-propoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s), and thelike,

yields, respectively,

1. 6'-fluorospiro[cyclohexan-1,1'(2'H)-naphthalen]-4-ol methanesulfonate(t),

2. 8'-propoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methanesulfonate(t), and the like.

EXAMPLE 19A A

3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yiazide(u)

A mixture of 5 g. (0.017 M) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methanesulfonate(t) (obtained in Example 18A) and 5 g. of sodium azide in 50ml. of dimethylformamide is heated in an oil bath at 90° C. for about 20hours. Most of the solvent is removed under vacuum and the residuedissolved in water and benzene. The organic layer is washed with waterand brine and evaporated to dryness to yield crude3',4'-dihydrospiro[cyclohexane-1,1(2'H)-naphthalen]-4-ylazide(u) as anoil.

Following the procedure of Example 19A but substituting other3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazides(t) asstarting materials, such as

1. 5'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-olmethanesulfonate(t),

2. 6'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-olmethanesulfonate(t), and the like,

yields, respectively,

1. 5'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u),

2. 6'-acetylamido[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u), andthe like.

EXAMPLE 20A

3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)]

A solution of the3',4'-dihydrospiro[cyclohexan-1,1'-(2'H)-naphthalen]-4-ylazide(u)obtained in Example 19A in 75 ml. of tetrahydrofuran, is added tosuspension of 0.65 g. of lithium aluminum hydride in 8 ml. oftetrahydrofuran, stirred at room temperature for about 5.5 hours andcooled in an ice bath. To this, 0.65 ml. of water, 0.65 ml. of 15%aqueous sodium hydroxide and 1.95 ml. of water are added successively.The resulting gel is collected on a filter, washed with ether and thefiltrates evaporated to dryness. The residue is dissolved in a smallamount of ether and an excess of 6.4 N hydrogen chloride in ether added.The precipitate is collected on a filter and recrystallized frommethanol:ethyl acetate to yield 1.76 g. of3',4'-dihydro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-aminehydrochloride[I(a)] melting at 271° to 273° C.

Following the procedure of Example 20A but substituting for hydrogenchloride another suitable (pharmacologically acceptable) acid, such ashydrobromic, sulfuric, phosphoric, nitric, benzoic, naphthoic,salicylic, tartaric, nicotinic, cyclohexanesulfamic, hexynoic, lactic,palmitic, glutaric, acetic, propionic, phenylbutyric acid, and the like,yields a corresponding acid addition salt of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine [I(a)].

Following the procedure of Example 20A but substituting another3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u) asstarting material, such as

1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u),

2. 6'-methoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u), andthe like,

yields, respectively,

1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)],

2. 6'-methoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)], and the like.

EXAMPLE 21A

1-[3',4'-Dihydrospiro(cyclohexane-1,1'(2'H)-naphthlen)-4-yl]piperidine[I(a)

The amine prepared from 1.5 g. of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride [I(a)] (obtained as in Example 20A), 1.9 g. of1.5-diiodopentane and 1.6 g. of potassium carbonate in 18 ml. of ethanolis stirred at reflux for about 18 hours. The mixture is allowed to cool,diluted with water, the solid collected on a filter and recrystallizedfrom methanol to give1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen4-yl]piperidine[I(a)].

Following the procedure of Example 21A but substituting the same andother (a) acid addition salts of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamines[I(a)]and (b) dihaloalkanes in stoichiometrically appropriate amounts asstarting materials, such as

1. 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)]and 1,4-dibromobutane,

2. 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)]and 1,6-diiodohexane,

3. 5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and1,5-diiodopentane,

4. 6'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and1,4-diiodobutane,

5. 7'-propoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and1,6-diiodohexane, and the like,

yields, respectively,

1.1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]pyrrolidine[I(a)],

2.1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]hexamethyleneimine[I(a)],

3.1-[5'-bromospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]piperidine[I(a)],

4.1-[6'-ethylspiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]pyrrolidine[I(a)],

5.1-[7'-propoxyspiro(cyclohexane-1,1'-(2'H)-naphthalen)-4-yl]hexamethyleneimine[I(a)],and the like.

EXAMPLE 22A

4'-Fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenonehydrochloride [I(a)]

A mixture of the free base prepared from 1 g. (0.00397 M) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride [I(a)] (obtained as in Example 20A), 0.81 g. of potassiumiodide, 1.24 g. of potassium carbonate and 1.4 g. of the2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in20 ml. of dimethylformamide is heated together in an oil bath at about90° C. for about 20 hours. The solvent is removed under vacuum and theresidue dissolved in water and benzene. The organic layer is washed withwater and brine and evaporated to dryness. A mixture of the residue, 8ml. of 2.5 N hydrochloric acid and 16 ml. of methanol is stirred at roomtemperature for about 2 hours and most of the methanol removed undervacuum. The residual suspended solid is collected on a filter, washedwith ether and recrystallized from methanol:ethyl acetate to give 0.65g. (39.5% yield) of4'-fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-amino]butyrophenonehydrochloride[I(a)], having a melting point of 194° to 197° C.

Anal. Calcd. for C₂₅ H₃₁ ClFNO: C, 72.18; H, 7.51; N, 3.37,

Found: C, 72.42; H, 7.66; N, 3.14.

Following the procedure of Example 22A but substituting another3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride [I(a)] as starting material, such as

1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)],

2. 6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)],

3. 7'-acetylamidospiro[cyclohexane-naphthalen]-4-ylaminehydrochloride[I(a)], and the like,

yields, respectively,

1.4'-fluoro-4-[5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenonehydrochloride[I(a)],

2.4'-fluoro-4-[6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenonehydrochloride[I(a)],

3.4'-fluoro-4-[7'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenonehydrochloride [I(a)], and the like.

Following the procedure of Example 22A but substituting another3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] asstarting material and the 2,2-dimethyl-1,3-propanediol ketal of anotherω-haloalkanaryl ketone, such as

1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of4'-bromo-4-chlorobutyrophenone,

2. 6'-methylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-4'-ethoxybutyrophenone,

3. 7'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of3',4-dichlorobutyrophenone,

4. 6'-propionylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of5-chloro-4'-ethylvalerophenone, and the like, yields, respectively,

1.4'-bromo-4-[5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenonehydrochloride[I(a)],

2.4'-ethoxy-4-[6'-methylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenonehydrochloride[I(a)],

3.3'-chloro-4-[7'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenonehydrochloride [I(a)],

4.4'-ethyl-5-[6'-propionylamido[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]valerophenone[I(a)],and the like.

EXAMPLE 23A

Ethyl3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)]

To an ice cooled solution of the free base prepared from 1.53 g. (0.0061M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylaminehydrochloride[I(a)] (obtained as in Example 20A) in 12 ml. of pyridine,0.95 ml. of ethyl chloroformate is added. The mixture is allowed tostand in the cold for about 5 hours and then poured in ice water. Thesolid that precipitates is collected on a filter and recrystallized frommethylene chloride:benzene to give 1.36 g. (77.7% yield) of ethyl3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-carbamate[I(a)],melting at 163.5° to 165° C.

Anal. Calcd. for C₁₈ H₂₅ NO₂ : C, 75.22; H, 8.77; N, 4.87

Found: C, 74.91; H, 8.77; N, 4.83.

Following the procedure of Example 23A but substituting another3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] asstarting material and another lower alkyl haloformate, such as

1. 5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] andmethyl chloroformate,

2. 6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] andpropyl bromoformate, and the like,

yields, respectively,

1. methyl5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)],

2. propyl6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)], andthe like.

EXAMPLE 24A

3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylaminehydrochloride [I(a)]

To a suspension of 0.22 g. (0.0058 M) of lithium aluminum hydride in 10ml. of tetrahydrofuran, a tetrahydrofuran solution of 1.3 g. (0.0045 M)of ethyl3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)](prepared as in Example 23A) is added. The mixture is stirred to refluxfor about 6 hours, at room temperature for about 18 hours, and thencooled in an ice bath. To this is added successively, 0.22 ml. of water,0.22 ml. 15% aqueous sodium hydroxide solution and 0.66 ml. of water.The resulting inorganic gel is collected on a filter, rinsed with etherand the filtrates evaporated to dryness. The residue is dissolved in asmall amount of ether and treated with an excess of 6.4 N hydrochloricacid in ether. The resulting precipitate is collected on a filter andrecrystallized from methanol:ethyl acetate to give 0.81 g. (52.7% yield)of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamine hydrochloride[I(a)], having a melting point of 285°to 286° C.

Anal. Calcd. for C₁₆ H₂₄ ClN: C, 72.29; H, 9.10; N, 5.25;

Found: C, 72.60; H, 9.16; N, 5.35.

Following the procedure of Example 24A but substituting another loweralkyl3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)]as starting material, such as

1. ethyl5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)],

2. propyl6'-propylspiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)], andthe like,

yields, respectively,

1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylaminehydrochloride[I(a)],

2. 6'-propylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylaminehydrochloride[I(a)], and the like.

EXAMPLE 25A

4'-Fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamino]-butyrophenonehydrochloride[I(a)]

A mixture of the free base prepared from 0.81 g. (0.00306 M) of3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen-4-yl-N-methylaminehydrochloride[I(a)] (obtained as in Example 24A), 0.63 g. of potassiumiodide, 0.96 g. of potassium carbonate and 0.87 g. of the2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in15 ml. of dimethylformamide is heated together in an oil bath at about90° C. for about 20 hours. The solvent is removed under vacuum and theresidue dissolved in water and benzene. The organic layer is washed withwater and brine and evaporated to dryness. A mixture of the residue, 6ml. of 2.5 N hydrochloric acid and 12 ml. of methanol is stirred at roomtemperature for about 1.5 hours and most of the methanol removed undervacuum. The residual suspended solid is collected on a filter, washedwith ether and recrystallized from methanol:ethyl acetate to give 0.59g. (44.8% yield) of4'-fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamino]butyrophenonehydrochloride[I(a)], having a melting point of 204° to 205.5° C.

Anal. Calcd. for C₂₆ H₃₃ ClFNO: C, 72.62; H, 7.74; N, 3.26,

Found: C, 72.69; H, 7.93; N, 3.03.

Following the procedure of Example 25A but substituting another3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-loweralkylamine[I(a)] as starting material and the2,2-dimethyl-1,3-propanediol ketal of another ω-haloalkyanaryl ketone,such as

1.5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamine[I(a)]and the 2,2-dimethyl-1,3-propane-diol of4'-butoxy-4-chlorobutyrophenone,

2.6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-ethylamine[I(a)]and the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-2'-methylbutyrophenone,

3.7'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamine[I(a)]and the 2,2-dimethyl-1,3-propanediol ketal of3-bromo-3'-chloropropiophenone,

4.8'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-ethylamine[I(a)]and the 2,2-dimethyl-1,3-propanediol ketal of5-fluoro-4'-propylvalerophenone, and the like,

yields, respectively,

1.4'-butoxy-4-[5'-chloropsiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamino]butyrophenonehydrochloride [I(a)],

2.2'-methyl-4-[6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-ethylamino]butyrophenonehydrochloride [I(a)],

3.3'-chloro-3-[7'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamino]propiophenonehydrochloride [I(a)],

4.4'-propyl-5-[8'-acetylamidospiro[cyclohexane-1,1'-(2'H)-naphthalen]-4-yl-N-ethylamino]valerophenonehydrochloride[I(a)], and the like.

EXAMPLE 1B

Methyl-4-hydroxycyclohexane carboxylate[2]

A solution of 200 g. of methyl-p-hydroxybenzoate[1] (prepared as in Ann.141, 247) in 1700 ml. of absolute ethanol has 66 g. of 5%rhodium/aluminum catalyst added thereto and then hydrogenated until nofurther uptake of hydrogen is observed. The catalyst is collected on afilter and the filtrate evaporated to dryness to yield 216 g. of crudemethyl-4-hydroxycyclohexane carboxylate(2), as an oil.

EXAMPLE 2B

4-Carbomethoxy-1-cyclohexanone[3]

The methyl-4-hydroxycyclohexane carboxylate prepared in Example 1B isdissolved in acetone with mechanical stirring and cooled in an ice bathto about 5° C. Jones reagent is added at a rate to keep the reactiontemperature below about 20° C. for about 10 minutes. Most of the solventis removed on a rotary evaporator and the residue taken up in 500 ml. ofether and 150 ml. of water. The organic layer is separated, washedsuccessively with water, saturated aqueous sodium bicarbonate solution,and brine and evaporated to dryness to yield an oil, which ondistillation under vacuum gives 47.4 g. of4-carbomethoxy-1-cyclohexanone[3] having a boiling point of 82° to 85°C. at 0.55 to 0.75 mm. of Hg.

EXAMPLE 3B

4-Carbomethoxy-1-cyclohexanone ethylene ketal[4]

A mixture of 189.7 g. of 4-carbomethoxy-1-cyclohexanone[3] (obtained asin Example 2B) in 2000 ml. of benzene, 67.5 ml. of ethylene glycol and2.7 g. of p-toluenesulfonic acid is heated at reflux under a Dean-Starktrap for about 5 hours. After cooling, the solution is washed withsaturated aqueous sodium bicarbonate and brine. The oily residueremaining when the organic solvent is evaporated to dryness is distilledunder vacuum to give 231.8 g. of 4-carbomethoxy-1-cyclohexanone ethyleneketal[4] having a boiling point of 95° to 100° C. at 0.30 mm. of Hg.

EXAMPLE 4B

4-Benzyl-4-carbomethoxy-1-cyclohexanone ethylene ketal[5]

To a solution of 5 g. (0.05 M) of diisopropyl amine in 50 ml. oftetrahydrofuran cooled in ice:methanol, 32 ml. of 1.57 N butyl lithiumin pentane is added over the course of about 5 minutes. There is thenadded, first, 10 g. (0.05 M) of 4-carbomethoxy-1-cyclohexanone ethyleneketal [4] (obtained as in Example 3B) in 50 ml. of tetrahydrufuran inthe course of about 15 minutes, and then 8.5 g. (0.05 M) ofα-bromotoluene (also named benzyl bromide) in 15 ml. of tetrahydrofuranin about 5 minutes. The clear solution is stirred at room temperaturefor about 1 hour, cooled in ice and treated with 50 ml. of saturatedammonium chloride solution. The organic layer is separated, diluted withbenzene and washed successively with water, ice cold N hydrochloric acidsolution, sodium bicarbonate solution and brine. The organic layer isevaporated to dryness and the oil that remains is distilled under vacuumto give 13.57 g. (93.5% of theoretical yield) of4-benzyl-4-carbomethoxy-1-cyclohexanone ethylene ketal[5] as a viscousoil having a boiling point of 155° to 156° C. at 0.25 mm. of Hg.

Anal. Calcd. for C₁₇ H₂₂ O₄ : C, 70.32; H, 7.64;

Found : C, 69.94; H, 7.60.

EXAMPLE 5B

4-(p-Methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5]

To a solution of 11.7 g. (0.112 M) of diisopropylamine in 115 ml. oftetrahydrofuran cooled in ice:methanol, 75 ml. of 1.67 N butyl lithiumin pentane is added over the course of about 12 minutes. There is thenadded, first, 23.1 g. (0.112 M) of 4-carbomethoxy-1-cyclohexanoneethylene ketal[5] (obtained as in Example 3B) in 115 ml. oftetrahydrofuran in the course of about 15 minutes, and then 14 g. (0.112M) of α-chloro-p-xylene in 115 ml. of tetrahydrofuran. The mixture isstirred in the cold for about 1 hour and at room temperature for about 2hours, and then 100 ml. of saturated aqueous ammonium chloride solutionand benzene added. The organic layer is separated, washed successivelywith water, 2.5 N hydrochloric acid solution, water and brine, and thenevaporated to dryness. The residue is distilled under vacuum to give21.47 g. (64% yield) of 4-(p-methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5] as a viscous oil havinga boiling point of 166° to 168.5° C. at 0.3 mm. of Hg.

Anal. Calcd. for C₁₈ H₂₄ O₂ : C, 71.02; H, 7.95; M.W. 304

Found: C, 71.23; H, 8.03; m/e 304.

EXAMPLE 6B

4-(m-Methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5]

To a solution of 10.1 g. (0.101 M) of diisopropylamine in 100 ml. oftetrahydrofuran cooled in ice:methanol, 62 ml. of 1.61 N butyl lithiumin pentane is added. There is then added, first 20 g. (0.10 M) of4-carbomethoxy-1-cyclohexanone ethylene ketal[4] (obtained as in Example3B) in 100 ml. of tetrahydrofuran in the course of about 12 minutes, andthen 18.5 g. of α-bromo-m-xylene in 100 ml. of tetrahydrofuran in about12 minutes. The mixture is stirred in the cold for about 1 hour and atroom temperature for about 1 hour, and then 100 ml. of saturatedammonium chloride solution and benzene added. The organic layer isseparated, washed successively with water, 2.5 N hydrochloric acidsolution, water, sodium bicarbonate solution and brine, and thenevaporated to dryness. The residue is distilled under vacuum to give21.32 g. (70% yield) of4-(m-methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5] as aviscous oil having a boiling point of 160° to 163° C. at 0.4 mm. of Hg.

Anal. Calcd. for C₁₈ H₂₄ O₄ : C, 71.02; H, 7.95; M.W. 304;

Found: C, 71.05; H, 8.12; m/e 304;

EXAMPLE 7B

4-(m-Methoxybenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5]

To an ice cooled solution of 10.25 g. (0.102 M) of diisopropylamine in100 ml. of tetrahydrofuran, 66 ml. of 1.67 N butyl lithium in pentane isadded. There is then added, first, 19.6 g. (0.0995 M) of4-carbomethoxy-1-cyclohexane ethylene ketal[4] (obtained as in Example3B) in 100 ml. of tetrahydrofuran in the course of about 10 minutes, andthen 15.3 g. of m-methoxylbenzyl chloride in 100 ml. of tetrahydrofuranin about 17 minutes. The mixture is stirred at room temperature forabout 2 hours and treated with 100 ml. of saturated ammonium chloridesolution and benzene. The organic layer is washed successively withwater, 2.5 N hydrochloric acid, water and brine, and then evaporated todryness. The residue is distilled under vacuum to give 22.32 g. (70%yield) of 4-(m-methoxybenzyl)-4-carbomethoxy-1-cyclohexanone ethyleneketal [5] having a boiling point of 159° to 165° C. at 0.2 mm. of Hg.

Anal. Calcd. for C₁₈ H₂₄ O₂ : C, 67.48; H, 7.55

Found: C, 67.71; H, 7.81.

Following the procedures of Examples 4B through 7B but substitutingother halides, such as

1. p-acetylamidobenzyl bromide,

2. m-chlorobenzyl bromide,

3. p-propylbenzyl bromide, and the like,

yields, respectively,

1. 4-(p-acetylamidobenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5] ,

2. 4-(m-chlorobenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal [5],

3. 4-(p-propylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal [5],and the like.

EXAMPLE 8B

1-Benzyl-4-cyclohexanone-1-carboxylic acid [7]

1. A mixture of 16.64 g. (0.057 M) of4-benzyl-4-carbomethoxy-1-cyclohexane ethylene ketal[5] (prepared as inExample 4B) and 2.5 g. of postassium hydroxide in 100 ml. ethyleneglycol is stirred at reflux for about 16 hours. The mixture is thenallowed to cool and diluted with water. The solution is washed once withwater and then made strongly acid with concentrated hydrochloric acid.The precipitated gum is extracted with ether and this solution washedfirst with water, then brine, and evaporated to dryness to give4-benzyl-4-carboxy-1-cyclohexanone ethylene ketal [6].

2. A solution of the residue [6] and 13 ml. of 2.5 N hydrochloric acidin 130 ml. of acetone is stirred at room temperature for about 20 hours,most of the solvent removed under vacuum and the residue dissolved inether. The organic layer is washed with water and brine and evaporatedto dryness. The residual gum is chromatographed on a column of 800 ml.of acid washed silica gel with elution by 4% acetic acid in methylenechloride. The crystalline fractions are combined and recrystallizedtwice from methylene chloride:cyclohexane to give 5.62 g. (42% yield) of1-benzyl-4-cyclohexanone-1-carboxylic acid[7] having a melting point of120° to 123° C.

Anal. Calcd. for C₁₄ H₁₆ O₂ : C, 72.39; H, 6.94

Found: C, 72.24; H, 6.86

EXAMPLE 9B

1-(p-Methylbenzyl)-4-cyclohexanone-1-carboxylic acid [7]

1. A mixture of 21.47 g. (0.0706 M) of4-(p-methyl-benzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal [5](prepared in Example 5B) and 2.5 g. of potassium hydroxide in 100 ml. ofethylene glycol is stirred at reflux for about 16 hours. The mixture isthen allowed to cool and diluted with water. The solution is washed oncewith water and then made strongly acidic with concentrated hydrochloricacid. The precipitated gum is extracted with ether and this solutionwashed with brine and evaporated to dryness to give4-(p-methylbenzyl)-4-carboxy-1-cyclohexanone ethylene ketal[6].

2. A solution of the residue[6] and 25 ml. of 2.5 N hydrochloric acid in200 ml. of acetone is stirred at room temperature for about 24 hours,most of the solvent removed under vacuum and the residue dissolved inether. The organic layer is washed with brine and evaporated to dryness.The residue is chromatographed on a column of 1,500 ml. of silica gelwith elution by 3% acetic acid in methylene chloride. The crystallinefractions are combined to give 6.8 g. (39% yield) of1-(p-methoxybenzyl)-4-cyclohexanone-1-carboxylic acid[7] as a waxysolid. A small sample is recrystallized from ether: petroleum ether togive crystals[7] having a melting point of 120° to 123° C.

Anal. Calcd. for C₁₅ H₁₈ O₃ : C, 73.14; H, 7.37

Found; C, 73.20; H, 7.60

EXAMPLE 10B

1-(m-Methylbenzyl)-4-cyclohexanone-1-carboxylic acid[7]

1. A solution of 21.31 g. (0.0701 M) of4-(m-methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5](prepared in Example 6B) and 3.4 g. of potassium hydroxide in 140 ml. ofethylene glycol is heated at reflux for about 20 hours. The mixture isthen allowed to cool, diluted with water and extracted with ether. Theaqueous layer is then made strongly acidic and the precipitated gumextracted with ether. This extract is washed with water and brine andevaporated to dryness to yield4-(m-methylbenzyl)-4-carboxy-1-cyclohexanone ethylene ketal[6].

2. A solution of the residue[6] and 25 ml. of 2.5 N hydrochloric acid in200 ml. of acetone is stirred at room temperature for about 16 hours,the solvent removed under vacuum and the residue extracted with ether.The extract is washed with water and brine and evaporated to dryness.The residue is chromatographed on 2000 ml. of acid washed silica gelwith elution by 4% acetic acid in methylene chloride. The fractionsfound similar by thin layer chromatography are combined to give 14.8 g.(56% yield) of 1-(m-methylbenzyl)-4-cyclohexanone-1-carboxylic acid[7]as a waxy solid.

EXAMPLE 11B

1-(m-Methoxybenzyl)-4-cyclohexanone-1-carboxylic acid[7]

1. A mixture of 24.3 g. (0.076 M) of4-(m-methoxybenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5](prepared as in Example 7B) and 4.35 g. of sodium hydroxide in 155 ml.of ethylene glycol is heated at reflux for about 42 hours. The mixtureis then diluted with water and washed with ether. The organic layer ismade acidic with hydrochloric acid the precipitated gum dissolved inether. The ether solution is washed with brine and evaporated to drynessto give 4-(m-methoxybenzyl)-4-carboxy-1-cyclohexanone ethylene ketal[6].

2. A solution of the residue and 27 ml. of 2.5 N hydrochloric acid in220 ml. of acetone is allowed to stand at room temperature for about 18hours, then most of the solvent removed under vacuum and the residuedissolved in ether. The organic layer is washed with brine andevaporated to dryness. The residue is chromatographed on a column ofacid washed silica gel with elution first by 0.5% acetic acid:methylenechloride then 2% acetic acid:methylene chloride. Those fractions foundsimilar by thin layer chromatography are combined, the solventevaporated and the resulting solid recrystallized twice from ether:Skellysolve B to give 7.18 g. (36% of theoretical yield) of1-(m-methoxy-benzyl)-4-cyclohexanone-1-carboxylic acid[7] having amelting point of 109 to 112.5° C. An additional 3.82 g. (19% yield) ofproduct [7] melting at 109° to 111° C. is obtained from the motherliquor.

Anal. Calcd. for C₁₅ H₁₈ O₄ : C, 68.68; H, 6.92

Found: C, 68.30; H, 6.92.

Following the procedures of Example 8B through 11B but substitutingother 4-benzyl-4-carbomethoxy-1-cyclohexanone ethylene ketals[5] asstarting materials, such as

1. 4-(o-methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5],

yields,

1. 1-(o-methylbenzyl)-4-cyclohexanone-1-carboxylic acid[7].

EXAMPLE 12B

Spiro(cyclohexane-1,2'-indan)-1',4-dione[8]

To 100 ml. of freshly distilled hydrogen fluoride, (14.63 M) of1-benzyl-4-cyclohexanone-1-carboxylic acid[7] (prepared as in Example8B) is added. The solution is allowed to stand at room temperature forabout 18 hours and then poured cautiously into saturated aqueous sodiumbicarbonate solution. The precipitated gum is extracted with benzene.The organic layer is washed successively with water, aqueous sodiumbicarbonate solution and brine, and then evaporated to dryness. Theresidue is chromatographed on a column of 1,500 ml. of silica gel withelution by 20% acetone in Skellysolve B. There is first obtained a smallamount of by-product followed by 10.5 g. (78%) ofspiro(cyclohexane-1,2'-indan)-1',4-dione[8], having a melting point of70.5° to 72° C.

Anal. Calcd. for C₁₄ H₁₄ O₂ : C, 78.48; H, 6.59

Found: C, 78.43; H, 6.59.

The less polar by-product is recrystallized from petroleum ether to give0.28 g. of a compound, which in view of its mass spectrum and elementalanalysis is spiro(cyclohexane-1,2'-indan)-4,4-difluoro-1'-one.

EXAMPLE 13B

5'-Methylspiro(cyclohexane-1,2'-indan)-1',4-dione[8]

To 50 ml. of freshly distilled hydrogen fluoride, 6.8 g. (0.026 M) of1-(p-methylbenzyl)-4-cyclohexanone-1-carboxylic acid [7] (prepared inExample 9B) is added. The solvent is allowed to evaporate over a periodof about 3 days. The residue is dissolved in ether and this solutionwashed successively with water, aqueous sodium bicarbonate solution andbrine. The solution is evaporated to dryness and the gum that remains ischromatographed on a column of 700 ml. of silica gel with elution by 20%acetone: Skellysolve B. The fractions found similar by thin layerchromatography are combined and rechromatographed on a column of 400 ml.of silica gel with elution by 20% acetone: Skellysolve B. Thecrystalline fractions are combined and recrystallized from acetone;Skellysolve B to give 2.06 g. (35% yield) of5'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione[8] having a meltingpoint of 110° to 113° C.

Anal. Calcd. for C₁₅ H₁₆ O₂ : C, 78.92; H, 7.06; M.W. 228.

Found: C, 78.92; H, 7.13; m/e 228.

EXAMPLE 14B

6'-Methylspiro(cyclohexane-1,2'-indan)-1',4-dione[8]

Onto 14.8 g. (0.060 M) of1-(m-methylbenzyl)-4-cyclohexanone-1-carboxylic acid[7] (prepared inExample 10B), 100 ml. of hydrogen fluoride is distilled. Following about2 days of standing at room temperature the solution is poured intosaturated aqueous sodium bicarbonate solution. The precipitate isdissolved in ether and the organic washed successively with water,saturated aqueous sodium bicarbonate solution and brine and evaporatedto dryness. The residue is chromatographed on a column of 1200 ml. ofFlorisil with elution by 10% acetone: Skellysolve B. The crystallinefractions are combined and recrystallized from acetone: Skellysolve B togive 7.3 g. (53% yield) of6'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione[8] having a meltingpoint of 121° to 122.5° C.

Anal. Calcd. for C₁₅ H₁₆ O₂ : C, 78.92; H, 7.01.

Found: C, 78.79; H, 7.22.

EXAMPLE 15B

5'-Methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione[8]

A suspension of 15.63 g. (0.060 M) of1-(m-methoxy-benzyl)-4-cyclohexanone-1-carboxylic acid [7] (prepared asin Example 11B) and 12.5 g. of phosphorus pentachloride in 190 ml. ofmonochlorobenzene is stirred mechanically under reflux for about 1.5hours and at room temperature for about 1.5 hours. The mixture is thencooled in ice and treated with 6.85 ml. of stannic chloride. After about0.5 hours of stirring in the cold and about 18 hours at roomtemperature, 96 ml. of 2.5 N hydrochloric acid is added in the course ofabout ten minutes. After about an additional hour of stirring, theorganic layer is separated, washed successively with water, aqueoussodium bicarbonate solution and brine and evaporated to dryness. Theresidue is chromatographed on a column of 1200 ml. of silica gel withelution by 10% ethyl acetate in methylene chloride. The crystallinefractions are combined to give 7.51 g. (51% yield) of5'-methoxyspiro[cyclohexane-1,2'-indan]-1',4-dione [8] having a meltingpoint of 105° to 107° C., and an analytic sample melting at 110° to 112°C.

Anal. Calcd. for C₁₅ H₁₆ O₃ : C, 73.75; H, 6.60; M.W. 244.

Found: C, 73.75; H, 6.65; m/e 244.

Following the procedures of Examples 12B through 15B but substitutingother 1-benzyl-4-cyclohexanone-1-carboxylic acids [7] as startingmaterials, such as

1-(p-ethylbenzyl)-4-cyclohexanone-1-carboxylic acid-[7], and the like,yields,

5'-ethylspiro(cyclohexane-1,2'-indan)-1',4-dione[8], and the like.

EXAMPLE 16B

Spiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal[ 9]

A mixture of 1.77 g. (0.0083 M) ofspiro(cyclohexane-1,2'-indan)-1',4-dione[8] (prepared as in Example 12B)0.51 g. (0.46 ml; 0.0082 M) of ethylene glycol and 0.1 g. ofp-toluenesulfonic acid in 50 ml. of benzene is heated at reflux under aDean-Stark trap for about 4 hours. The mixture is allowed to cool,washed successively with aqueous sodium bicarbonate solution, water andbrine and evaporated to dryness. The residual solid is recrystallizedfrom cyclohexane to give 1.67 g. (75% yield) ofspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal[ 9], having amelting point of 158° to 160.5° C; ν_(max). 1690 ^(cm) ⁻ 1.

Anal. Calcd. for C₁₆ H₁₈ O₃ : C, 74.39; H, 7.02; M.W. 258.

Found: C, 73.99; H, 6.98; m/e 258.

EXAMPLE 17B 5'-Methylspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethyleneketal [9]

A mixture of 2.06 g. (0.00905 M) of5'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione [8 ] (prepared inExample 13B), 0.56 g. (0.50 ml.) of ethylene glycol and 0.1 g. ofp-toluenesulfonic acid in 50 ml. of benzene is heated at reflux under aDean-Stark trap for about 2 hours. The mixture is allowed to cool,washed with aqueous sodium bicarbonate solution then water andevaporated to dryness. The residual solid is recrystallized frommethylene chloride: cyclohexane to give 1.96 g. (86%) of5'-methyl-spiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal-[9],melting at 124° to 127° C.

Anal. Calcd. for C₁₇ H₂₀ O₃ : C, 74.97; H, 7.40.

Found: C, 74.97; H, 7.51.

Example 18B

6'-Methylspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9]

A mixture of 7.3 g. (0.032 M) of6'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione [8] (prepared inExample 14B), 2.15 g. (1.95 ml.) of ethylene glycol and 0.5 g. ofp-toluenesulfonic acid in 200 ml. of benzene is heated at reflux under aDean-Stark trap for about 5 hours. The mixture is allowed to cool,washed successively with aqueous sodium bicarbonate solution, water andbrine and evaporated to dryness. The residual solid is recrystallizedfrom methylene chloride: Skellysolve B to give 7.94 g. (91% yield) of6'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9]melting at 116° to 118° C.

Anal. Calcd. for c₁₇ H₂₀ O₃ : C, 74.97; H, 7.40.

Found: C, 75.33; H, 7.65.

EXAMPLE 19B

5'-Methoxyspiro(cyclohexane-1,2'-indan)-1', 4-dione 4-ethylene ketal [9]

A mixture of 4.89 g. (0.0196 M) of6'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione [8] (prepared as inExample 15B), 1.21 g. of ethylene glycol and 0.2 g. of p-toluenesulfonicacid in 100 ml. of benzene is heated at reflux under a Dean-Stark trapfor about 5 hours. The mixture is allowed to cool, washed with aqueoussodium bicarbonate solution and evaporated to dryness. The residue isrecrystallized twice from methylene chloride: Skellysolve B to give 4.13g. (73% yield) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione4-ethylene ketal [9 ] having a melting point of 142° to 144° C.

Anal. Calcd. for C₁₇ H₂₀ O₄ : C, 70.81; H, 6.99.

Found: C, 71.06; H, 7.19.

Following the procedures of Examples 16B through 19B but substitutingother spiro(cyclohexane-1,2'-indan)-1',4-diones [8] as startingmaterials, such as

1. 7'-acetylamidospiro(cyclohexane-1,2'-indan)-1',4-dione[8],

2. 5'-ethoxyspiro(cyclohexane-1,2'-indan)1', 4-dione [8], and the like,

yields, respectively,

1. 7'-acetylamidospiro(cyclohexane-1,2'-indan)- 1', 4-dione 4-ethyleneketal [9],

2. 5'-ethoxyspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal[9], and the like.

EXAMPLE 20B

Spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10]

A mixture of 5g. (0.0194 M) of spiro(cyclohexane 1,2'-indan)-1',4-dione4-ethylene ketal [9](prepared as in Example 16B), 2.6ml. of hydrazinehydrate and 3.76 g. of potassium hydroxide in 50 ml. of ethylene glycolis heated at reflux for about 1.5 hours. Material is then removed bydistillation to bring the pot temperature to 200° C. After about 5 hoursof additional heating at reflux, the mixture is allowed to cool anddiluted with water. The precipitated solid is collected on a filter,dried and recrystallized from petroleum ether to give 4 g. (85% yield)of spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10], having amelting point of 70° to 74° C.

Anal. Calcd. for C₁₆ H₂₀ O₂ : C, 78.65; H, 8.25.

Found: C, 78.39; H, 8.19.

EXAMPLE 21B

5'-Methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10]

A mixture of 7.3 g. (0.027 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-1', 4-dione 4-ethylene ketal [9] (prepared as in Example17B), 3.8 ml. of hydrazine hydrate and 5.52 g. of potassium hydroxide in70 ml. of ethylene glycol is heated at reflux for about 1 hour. Materialis then removed by distillation to bring the pot temperature to 200° C.Following about 18 hours of heating at reflux the mixture is allowed tocool and poured into water and extracted with ether. The organic extractis washed with water and brine and evaporated to dryness, to give5'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10].

EXAMPLE 22B

6'-Methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10]

A mixture of 7.3 g. (0.027 M) of6'-methylspiro(cyclohexane-1,2'-indan)-1', 4-dione 4-ethylene ketal [9](prepared as in Example 18B), 3.8 ml. of hydrazine hydrate and 5.52 g.of potassium hydroxide in 70 ml. of ethylene glycol is heated at refluxfor about 1 hour. Material is then removed by distillation to bring thepot temperature to 200° C. Following about 18 hours of heating at refluxthe mixture is allowed to cool and poured into water. The precipitatedoil is extracted with ether. This organic extract is washed with waterand brine and evaporated to dryness, to give 7.01 g. (about 99% yield)of 6'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10]having a melting point of 37+ to 41° C. This material, having a nuclearmagnetic resonance (NMR) spectrum in agreement with the expectedstructure, is not satisfactorily recrystallized.

EXAMPLE 23B

5'-Methoxyspiro(cyclohexane-1',2-indan)-4-one ethylene ketal [10]

A mixture of 4.57 g. (0.0158 M) of5'-methoxyspiro-(cyclohexane-1,2'-indan)-1',4 -dione 4-ethylene ketal[9] (prepared as in Example 19B), 2.45 g. of hydrazine hydrate and 3.15g. of potassium hydroxide in 40 ml. of ethylene glycol is heated atreflux for about 1 hour. Solvent is removed by distillation to bring thereaction mixture to 200° C. Following about 1.5 hours at thistemperature the mixture is poured into water and well extracted withether. The ether extracts are combined and evaporated to dryness. Theresidue is chromatographed on a 250 ml. column of silica gel withelution by 10% acetone in Skellysolve B to give 2.07 g. (48% yield) of5'-methoxyspiro(cyclohexane-1',2-indan)-4-one ethylene ketal [10] havinga melting point of 59° to 61° C. The analytical sample from an earlierexperiment melted at 65° to 66.5° C.

Anal. Calcd. for C₁₇ H₂₂ O₃ : C, 74.22; H, 8.08.

Found: C, 74.57; H, 8.24.

The aqueous portion (i.e., not extracted by ether), above, is"acidified" with solid carbon dioxide. The precipitated solid iscollected on a filter and recrystallized from methanol to give 0.51 g.of by-product, 5"-hydroxydispiro[1,3-dioxolane-2,1'-cyclohexane-4',2"-indan]-1"-one hydrazone, havingmelting ranges of 243° to 246° C. and 285° to 290° C.

Anal. Calcd. for C₁₆ H₂₀ N₂ O₃ : C, 66.69; H, 6.99; N, 9.71; M.W. 288.

Found; C, 66.16; H, 7.14; N, 9.96; m/e 288.

Following the procedures of Example 20B through 23B but substitutingother spiro(cyclohexane-1,2'-indan)-1', 4-dione 4-ethylene ketals [9]asstarting materials, such as

5'-chlorospiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9],and the like, yields,

5'-chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10], andthe like.

Example 24B

Spiro(cyclohexane -1,2'-indan)-4-one, oxime [12 ]

1. A mixture of 4g. (0.016 M) of spiro(cyclohexane-1,2'-indan)-4-oneethylene ketal [10] (prepared in Example 20B) and 8 ml. of 2.5 Nhydrochoric acid in 80 ml. of acetone is heated at reflux for about 4hours. Most of the solvent is removed under vacuum and ether added. Theorganic layer is separated, washed with water and brine and evaporatedto dryness. The residue is chromatographed on a 350 ml. column of silicagel with elution by methylene chloride. Those fractions similar by thinlayer chromatography are combined to givespiro(cyclohexane-1,2'-indan)-4-one [11] as an amorphous gum.

2. A mixture of the gum [11] obtained in (1), above, 3 g. ofhydroxylamine hydrochloride and 10 ml. of water in 100 ml. oftetrahydrofuran is heated at reflux for about 15 hours. Most of thesolvent is removed under vacuum and the residue diluted with water. Theprecipitated solid is recrystallized from cyclohexanone to give 3.1 g.(90% yield) of spiro(cyclohexane-1,2'-indan)-4-one oxime [12] having amelting point of 120° to 122° C.

Anal. Calcd. for C₁₄ H₁₇ NO: C, 78.10; H, 7.96; N, 6.51.

Found: C, 78.08; H, 7.85; N, 6.50.

Following the procedure of Example 24B but substituting otherspiro(cyclohexane-1,2'-indan)-4-one ethylene ketals [10] as startingmaterials, such as

1. 7'-bromospiro(cyclohexane-1,2'-indan)-4-one, ethylene ketal [10],

2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-one, ethylene ketal [10],

3. 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one, ethylene ketal [10],and the like, yields, respectively,

1. 7'-bromospiro(cyclohexane-1,2'-indan)-4-one [11] and its oxime [12],

2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-one [11] and its oxime [12],

3. 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one-[11] and its oxime[12], and the like.

EXAMPLE 25B

Spiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13 ]

A solution of 3.1 g. spiro(cyclohexane-1,2'-indan)-4-one oxime [12](prepared in Example 24B) and 6 ml. of acetic anhydride in 25 ml. ofpyridine is allowed to stand at room temperature for about 6 hours. Thereaction mixture is then poured into ice: water and the solid collectedon a filter. The solid is recrystallized from Skellysolve B to give 2.94g. (88% yield) of spiro(cyclohexane-1,2'-indan)-4-one, oxime acetate[13] having a melting point of 91° to 94° C.

Anal. Calcd. for C₁₆ H₁₉ NO₂ : C, 74.68; H, 7.44; N, 5.44.

Found: C, 74.43; H, 7.35; N, 5.49.

Following the procedure of Example 25B but substituting otherspiro(cyclohexane-1,2'-indan)-4-one oximes [12] as starting materials,such as

1. 6'-chlorospiro(cyclohexane-1,2'-indan)-4-one, oxime [12],

2. 7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-one, oxime [12], and thelike,

yields, respectively,

1. 6'-chlorospiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13],

2. 7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13], andthe like.

EXAMPLE 26B

Sprio(cyclohexane-1,2'-indan)-4-amine hydrochloride-[I (b) ]

To an ice-cooled solution of 2.94 g. (0.0114 M) ofspiro(cyclohexane-1,2'-indan)-4-one oxime acetate [13 ](prepared inExample 25B) in 50ml. of tetrahydrofuran, 15 ml. of N diborane intetrahydrofuran is added dropwise. Following about 6 hours of standingin the cold, 1 ml. of water is added. The solvent is then removed undervacuum and the residue stirred for about 1 hour at room temperature with90 ml. of 2.5 N hydrochloric acid covered by ether. The aqueous layer isthen made strongly basic, the organic layer washed with water and brineand evaporated to dryness. The residue is dissolved in ether and thissolution treated with 5 N hydrochloric acid in ether. The resultingprecipitate is recrystallized from methanol: ethyl acetate to give 1.12g. (41% yield) of spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b) ], having a melting point of 270° to 273° C.

Anal. Calcd. for C₁₄ H₂₀ ClN: C, 70.71; H, 8.48; N, 5.89.

Found: C, 70.68; H, 8.55; N, 5.69.

Following the procedure of Example 26B but substituting otherspiro(cyclohexane-1,2'-indan)-4-one acetate oximes [13] as startingmaterials, such as

1. 5'-bromospiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13],

2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13],

3. 7'-methoxyspiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13],and the like,

yields, respectively,

1. 5'-bromospiro(cyclohexane-1,2'-indan)-4-amine [I (b) ],

2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-amine [I (b) ],

3. 7'-methoxyspiro(cyclohexane-1,2'-indan)-4-amine [I (b) ], and thelike.

EXAMPLE 27B

Spiro(cyclohexane-1,2'-indan)-4-ol [14]

To a solution of 8.33 g. (0.042 M) of crudespiro(cyclohexane-1,2'-indan)-4-one[11] [obtained as in (1) of Example23B] in 85 ml. of ethanol, 1.6 g. of sodium borohydride is added.Following about 6 hours of stirring at room temperature, most of thesolvent is removed under vacuum. The residue is suspended in ether andwater. The organic layer is washed with water and brine and evaporatedto dryness. The residue is chromatographed on a column of 800 ml. ofsilica gel with elution by 10% acetone in methylene chloride. Thecrystalline fractions are combined and recrystallized from petroleumether to give 5.52 g. (66% yield) of spiro(cyclohexane-1,2'-indan)-4-ol[14] having a melting point of 76° to 78° C.

Anal. Calcd. for C₁₄ H₁₈ O: C, 83.12; H, 8.97.

Found: C, 83.33; H, 8.92.

Following the procedure of Example 27B but substituting otherspiro(cyclohexane-1,2'-indan)-4-ones [11] as starting materials, such as

1. 5'-chlorospiro(cyclohexane-1,2'-indan)-4-one [11],

2. 6'-ethoxyspiro(cyclohexane-1,2'-indan)-4-one [11], and the like,

yields, respectively,

1. 5'-chlorospiro(cyclohexane-1,2'-indan)-4-ol [14],

2. 6'-ethoxyspiro(cyclohexane-1,2'-indan)-4-ol [14], and the like.

EXAMPLE 28B

5'-Methylspiro(cyclohexane-1,2'-indan)-4-ol [14]

1. A solution of 7.01 g. (0.027 M) of5'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10](obtained as in Example 21B) and 10 ml. of 2.5 N hydrochloric acid in100 ml. of acetone is allowed to stand at room temperature for about 17hours. The solvent is then removed under vacuum and the residuesuspended in water and ether. The organic layer is washed with water andbrine and evaporated to dryness. The residue is chromatographed on acolumn of silica gel with elution by 10% acetone: Skellysolve B. Thecrystalline fractions are combined and recrystallized from petroleumether to give 4.43 g. (76% yield) of5'-methyl(cyclohexane-1,2'-indan)-4-one [11], melting at 68° to 70° C.

Anal. Calcd. for C₁₅ H₁₈ O: C, 84.07; H, 8.47.

Found: C, 83.92; H, 8.79.

2. To a solution of 4.43 g. of the5'-methylspiro(cyclohexane-1,2'-indan)-4-one [11] obtained in (1),above, in 100 ml. of 95% isopropanol, 0.8 g. of sodium borohydride isadded. Following about 5.5 hours of standing at room temperature most ofthe solvent is removed under vacuum. The residue is dissolved in waterand ether. The organic layer is washed with water and brine and thenevaporated to dryness, to give 4.55 g. (97%) of5'-methylspiro(cyclohexane-1,2'-indan)-4-ol[ 14] as a gum which showed asingle spot on thin layer chromatography.

EXAMPLE 29B

5'-Methoxyspiro(cyclohexane-1,2'-indan)-4-ol[ 14]

1. A solution of 2.87 g. (0.0105 M) of5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[ 10](obtained as in Example 23B) and 6.5 ml. of 2.5 N hydrochloric acid in60 ml. of acetone is allowed to stand at room temperature for about 18hours. Most of the solvent is removed under vacuum and the residuedissolved in water and ether. The organic layer is washed with water andbrine and evaporated to dryness. The residue is recrystallized fromSkellysolve B to give 1.95 g. (81% yield) of5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one[ 11] melting at 89° to 91°C.

Anal. Calcd. for C₁₅ H₁₈ O₂ : C, 78.23; H, 7.88.

Found: C, 77.96; H, 7.96.

2. A suspension of 1.95 g. of the5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one[ 11] obtained in (1),above, in 100 ml. of isopropanol is warmed to bring the solid intosolution. There is then added 0.35 g. of sodium borohydride and themixture stirred at room temperature for about 7 hours. Most of thesolvent is removed under vacuum and the residue dissolved in water andether. The residue is washed with water and brine and evaporated todryness. The product, 1.86 g. of5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ol[ 14], is an oil having anuclear magnetic resonance (NMR) spectrum in agreement with the expectedstructure.

Following the procedures of Examples 28B and 29B but substituting otherspiro(cyclohexane-1,2'-indan)-4-one ethylene ketals[ 10] as startingmaterials, such as

7'-fluorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[ 10], andthe like, yields,

7'-fluorospiro(cyclohexane-1,2'-indan)-4-ol[ 14], and the like.

EXAMPLE 30B

Spiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15]

A mixture of 5.52 g. (0.027 M) ofspiro(cyclohexane-1,2'-indan)-[4-ol[14] (obtained in Example 27B) in 50ml. of ice cold pyridine is treated with 5.5 ml. of methane sulfonylchloride. After standing for about 7 hours in the cold the mixture isdiluted with ice: water. The precipitated solid is recrystallized fromacetone: Skellysolve B to give 7.15 g. (93% yield) of spiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15], melting at 100° to 102° C.

Anal. Calcd. for C₁₅ H₂₀ O₃ S: C, 64.25; H, 7.19.

Found; C, 63.87; H, 7.50.

EXAMPLE 31B

5'-Methylspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15]

To an ice cold solution of 4.55 g. (0.021 M) of5'-methylspiro(cyclohexane-1,2'-indan)-4-ol[ 14] (obtained in Example28B) in 40 ml. of pyridine, 4.5 ml. of methanesulfonyl chloride isadded. After standing about 5 hours in the cold the mixture is pouredinto ice: water. The precipitated gum is extracted with ether and theextract washed successively with water, 2.5 N hydrochloric acid, waterand brine. The extract is evaporated to dryness and the solid thatremains is recrystallized from ether: petroleum ether to give 5.38 g.(83%) of 5'-methylspiro(cyclohexane)-1,2'-indan)-4-ol methanesulfonate[15], melting at 64° to 66° C.

Anal. Calcd. for C₁₆ H₂₂ O₃ S: C, 65.27; H, 7.53.

Found: C, 65.41; H, 7.69.

EXAMPLE 32B

5'-Methoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15 ]

An ice cold solution of 1.86 g. (0.008 M) of5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ol[14] (obtained in Example29B) in 18 ml. of pyridine is treated with 2 ml. of methane sulfonylchloride. After standing for about 5 hours in the cold the mixture ispoured onto ice: water. The precipitated solid is recrystallized frommethylene chloride: Skellysolve B to give 2.1 g. (85% yield) of5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15],melting at 63° to 67° C.

Anal. Calcd. for C₁₆ H₂₂ O₄ S: C, 61.91; H, 7.14.

Found: C, 61.80; H, 7.14.

Following the procedures of Example 30B through 32B but substitutingother spiro(cyclohexane-1,2'-indan)-4 -ols[ 14] as starting materials,such as

1. 5'-bromospiro(cyclohexane-1,2'-indan)-4-ol[14],

2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-ol[14],

3. 7'-isopropoxyspiro(cyclohexane-1,2'-indan)-4-ol-[14], and the like,

yields, respectively,

1. 5'bromospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15],

2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [15],

3. 7'-isopropoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[15], and the like.

EXAMPLE 33B

Spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride I(b)]

1. A mixture of 7.15 g. (0.0256 M) of spiro(cyclohexane-1,2'-indan)-4-olmethanesulfonate[ 15] (obtained in Example 30B) and 7 g. of sodium azidein 70 ml. of dimethylformamide is stirred in an oil bath at about 90° C.for about 17 hours. The solvent is then removed under vacuum and theresidue dissolved in benzene and water. The organic layer is washed withwater and brine to give spiro(cyclohexane-1,2'-indan)-4-ylazide[ 16].

2. A solution of the crude spiro(cyclohexane-1,2'-indan)-4ylazide[ 16]obtained in (1), above, in 75 ml. of tetrahydrofuran is added to a wellstirred suspension of 1 g. of lithium aluminum hydride in 25 ml. oftetrahydrofuran. Following about 5 hours of stirring at room temperaturethe mixture is cooled in ice and treated successively with 1 ml. ofwater, 1 ml. of 15% aqueous sodium hydroxide solution and 3 ml. ofwater. The inorganic gel is removed by filtration and the filtrateevaporated to dryness. The residue is dissolved in ether and thissolution treated with 5 N hydrogen chloride in ether. The precipitatedsolid is recrystallized from methanol: ethyl acetate to give 4.58 g.(76% yield) of spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] , melting at 280° to 282° C.

EXAMPLE 34B

5'-Methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)]

1. A mixture of 5.38 g. (0.0183 M) of5'-methylspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15](prepared in Example 31B) and 5.4 g. of sodium azide in 55 ml. ofdimethylformamide is stirred in an oil bath at about 100° C. for about18 hours. The solvent is removed under vacuum and the residue dissolvedin benzene and water. The organic layer is washed with water and brineand evaporated to dryness to give5'-methylspiro(cyclohexane-1,2'-indan)-4-ylazide[16].

2. A solution of the 5'-methylspiro(cyclohexane-1,2'-indan)-4-ylazide[16] obtained in (1), above, in 60 ml. of tetrahydrofuran is added to awell stirred suspension of 0.75 g. of lithium aluminum hydride in 20 ml.of tetrahydrofuran in the course of about 30 minutes. After about 4hours the mixture is cooled in ice and treated successively with 0.75ml. water, 0.75 ml. of 15% aqueous sodium hydroxide solution and 2.25ml. of water. The inorganic gel is removed by filtration, rinsed withmethylene chloride and ether and the filtrate evaporated to dryness. Theresidue is dissolved in ether and the solution treated with 5 N hydrogenchloride in ether. The precipitated solid is recrystallized frommethylene chloride: ethyl acetate to give 3.89 g. (85%) of5'-methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] ,melting at 248° to 252° C.

Anal. Calcd. for C₁₅ H₂₂ ClN: C, 71.54; H, 8.81; N, 5.56.

Found: C, 71.19; H, 8.85; N, 5.42.

EXAMPLE 35B

5'-Methoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)]

1. A mixture of 2.1 g. (0.0068 M) of5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15](obtained in Example 32B) and 2.1 g. of sodium azide in 20 ml. ofdimethylformamide is stirred in an oil bath at about 90° C. for about 16hours. The solvent is removed under vacuum and the residue dissolved inbenzene and water. The organic layer is washed with water and brine andevaporated to dryness to give5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ylazide[ 16].

2. A solution of the 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ylazide[16] obtained in (1), above, in 50 ml. of tetrahydrofuran to 0.26 g. oflithium aluminum hydride in 8 ml. of tetrahydrofuran in the course ofabout 10 minutes. Following about 4.5 hours of stirring at roomtemperature the mixture is cooled in ice and there is added successively0.26 ml. of water, 0.26 ml. of 15% aqueous sodium hydroxide solution and0.78 ml. of water. The inorganic gel is collected on a filter and thefiltrate evaporated to dryness. A solution of the residue in ether istreated with 6 N hydrogen chloride in ether. The precipitated solid isrecrystallized from methanol: methylene chloride: ethyl acetate to give0.69 g. (38% yield) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[ I(b)] , having a melting point of 274° to 277° C.

Anal. Calcd. for C₁₅ H₂₂ ClNO: C, 67.27; H, 8.28; N, 5.23.

Found: C, 67.25; H, 8.18; N, 4.98.

Concentration of the mother liquors gives 0.43 g. (23%) of an apparentlypolymorphic form of the product [I(b)] , having a melting point of 246°to 248° C.

Anal. Found: C, 66.98; H, 8.50; N, 4.87; m/e 231.

Following the procedures of Examples 33B through 35B but substitutingother spiro(cyclohexane-1,2'-indan)-4-ol methanesulfonates[ 15] asstarting materials, such as

1. 5'-fluorospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15],

2. 6'-isopropylspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15],and the like,

yields, respectively,

1. 5'-fluorospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] ,

2. 6'-isopropylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] , and the like.

Following the procedures of the immediately preceding paragraph and ofExamples 33B through 35B but substituting other pharmacologicallyacceptable acids for hydrogen chloride, e.g., sulfuric, nitric, acetic,citric, benzoic, nicotinic, and the like, yields correspondingspiro(cyclohexane-1,2'-indan)-4-amine acid addition salts[ I(b)] .

EXAMPLE 36B

1-Spiro(cyclohexane-1,2'-indan)-4-yl piperidine hydrochloride[ I(b)]

To a suspension of 1.53 g. (0.0065 M) ofspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] (prepared asin Example 33B) in 30 ml. of ethanol, there is added 1.58 ml. of 4.2 Nsodium methoxide in methanol. Following about 1 hour of stirring, 1.62g. of potassium carbonate and 0.97 ml. of 1,5-diiodopentane is added andthe mixture heated to reflux. After about 18 hours the mixture isallowed to cool and most of the solvent removed under vacuum. Theresidue is partitioned between ether and water, the organic layer washedwith water and brine and then evaporated to dryness. The residual solidis dissolved in ether and this solution treated with 5 N hydrogenchloride in ether. The resulting precipitate is recrystallized frommethylene chloride: ethyl acetate to give 1.53 g. (77% of theoreticalyield of 1-spiro(cyclohexane-1,2'-indan)-4-yl piperidine hydrochloride[I(b)] , having a melting point of 282° to 286° C.

Anal. Calcd. for C₁₉ H₂₈ ClN: C, 74.60; H, 9.23; N, 4.58.

Found: C, 74.13; H, 9.27; N, 4.71.

Following the procedure of Example 36B but substituting the same andother (a) acid addition salts of spiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and (b) the same and other dihaloalkanes in stoichiometricallyappropriate amounts as starting materials, such as

1. spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [ I(b)] and1,4-dibromobutane,

2. spiro(cyclohexane-1,2'-indan)-4-amine hydrobromide [ I(b)] and1,6-diiodohexane,

3. 5'-chlorospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)]and 1,5-diiodopentane,

4. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-amine nitrate[ I(b)] and1,4-diiodobutane, and the like, yields, respectively,

1. 1-spiro(cyclohexane-1,2'-indan)-4-yl pyrrolidine hydrochloride[ I(b)],

2. 1-spiro(cyclohexane-1,2'-indan)-4-yl hexamethyl-eneiminehydrochloride[ I(b)] ,

3. 1-[5'-chlorospiro(cyclohexane-1,2'-indan)-4-yl] piperidinehydrochloride[ I(b)] ,

4. 1-[6'-ethylspiro(cyclohexane-1,2'-indan)-4-yl]-pyrrolidinehydrochloride[ I(b)] , and the like.

EXAMPLE 37B

4'-Fluoro-4-[[spiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[ I(b)]

To a solution of 1.12 g. (0.0047 M) ofspiro(cyclohexan-1,2'-indan)-4-amine hydrochloride[ I(b)] (prepared asin Example 33B) in 30 ml. of dimethylformamide, there is added 0.22, g.of sodium hydride. Following about 1 hour of stirring at roomtemperature, 0.81 g. of potassium iodide, 1.32 g. of potassium carbonateand 1.14 g. of the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-4'-fluorobutyrophenone are added. The mixture is then stirredin an oil bath for about 18 hours at about 90° C. The solvent is removedunder vacuum and the residue dissolved in benzene and water. The organiclayer is washed with water and brine and evaporated to dryness. Theresidue is then stirred with 15 ml. of methanol and 7.5 ml. of 2.5 Nhydrochloric acid for about 2 hours. Most of the methanol is removedunder vacuum and the solid collected on a filter. Two recrystallizationsfrom methylene chloride: ethyl acetate give 0.84 g. (46% yield) of4'-fluoro-4-[[spiro[cyclohexane-1,2'-indan]-4-yl]aminobutyrophenonehydrochloride[ I(b)] , having a melting point of 195° to 198° C.

Anal. Calcd. for C₂₄ H₂₉ ClFNO: C, 71.71; H, 7.27.

Found: C, 71.68; H, 7.14.

EXAMPLE 38B

4'-Fluoro-4-[[5'-methylspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)]

A suspension of 1.5 g. (0.0049 M) of5'-methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](prepared as in Example 34B) in 30 ml. of methylene chloride is shakenwith 25 ml. of N sodium hydroxide solution until all the solid isdissolved. The organic layer is separated and evaporated to dryness. Toa solution of the residue in 25 ml. of dimethylformamide, 1 g. ofpotassium iodide, 1.53 g. of potassium carbonate and 1.41 g. of the2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenoneare added. Following about 18 hours of heating in an oil bath at about90° C., the solvent is removed under vacuum. The residue is dissolved inbenzene and water, the organic layer washed with water and brine andthen evaporated to dryness. A mixture of the residue in 10 ml. of 2.5 Nhydrochloric acid and 20 ml. of methanol is stirred for about 2 hours atroom temperature. Most of the methanol is then removed under vacuum andthe solid collected on a filter. This is recrystallized from methanol:ethyl acetate to give 0.61 g. (30% yield) of4'-fluoro-4-[[5'-methylspiro[cyclohexane-1,2'-indan]-4-yl]-amino]butyrophenonehydrochlorde[I(b)], melting at 204° to 206° C.

Anal. Calcd. for C₂₅ H₃₁ ClFNO: C, 72.18; H, 7.51; N, 3.37.

Found: C, 72.28; H, 7.73; N, 3.29.

EXAMPLE 39B

4'-Fluoro-4-[[5'-methoxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)]

A suspension of 0.69 g. (0.0026 M) of5'-methoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](prepared in Example 35B) in 15 ml. of methylene chloride is shaken with10 ml. of N sodium hydroxide solution until all of the solid isdissolved. The organic layer is separated and evaporated to dryness. Toa solution of the residue in 15 ml. of dimethylformamide, 0.52 g. ofpotassium iodide, 0.81 g. of potassium carbonate and 0.75 g. of the2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenoneare added. After about 18 hours of heating at about 90° C., the solventis removed under vacuum. The residue is dissolved in benzene and water,the organic layer washed with water and brine and evaporated to dryness.The residue is dissolved in 5 ml. of 2.5 N hydrochloric acid and 10 ml.of methanol. After standing for about 3 hours at room temperature mostof the methanol is removed under vacuum. The solid that precipitates isrecrystallized from methylene chloride: ethyl acetate to give 0.52 g.(46%) of4'-fluoro-[[5'-methoxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)], melting at 190° to 193° C.

Anal. Calcd. for C₂₅ H₃₁ ClFNO₂ : C, 69.51; H, 7.23; N, 3.24.

Found: C, 69,62; H, 7.20; N, 3.11.

Following the procedures of Examples 37B through 39B but substitutingthe same and other (a) acid addition salts ofspiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and (b) the2,2-dimethyl-1,3-propanediol ketals of the same and otherω-haloalkanaryl ketones in stoichiometrically appropriate amounts asstarting materials, such as

1. spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)] and the2,2-dimethyl-1,3-propanediol ketal of 3-bromo-4'-ethylpropiophenone,

2. 7'-chlorospiro(cyclohexane-1,2'-indan)-4-amine hydrobromide[I(b)] andthe 2,2-dimethyl-1,3-propanediol ketal of 3',4-dichlorobutyrophenone,

3. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] andthe 2,2-dimethyl-1,3-propanediol ketal of4-chloro-2'-ethoxybutyrophenone,

4. 4'-acetylamidospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of5-chloro-4'-ethylvalerophenone, and the like,

yields, respectively,

1. 4'-ethyl-3[[spiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenonehydrochloride[I(b)],

2.3'-chloro-4-[[7'-chlorospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)],

3.2'-ethoxy-4-[[6'-ethylspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)],

4.4'-ethyl-5-[[4'-acetylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]valerophenonehydrochloride[I(b)], and the like.

EXAMPLE 40B

Ethyl spiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]

A suspension of 3.03 g. (0.0128 M) ofspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared asin Example 33B) in 65 ml. of methylene chloride is shaken with 50 ml. ofN sodium hydroxide solution until the solid is completely dissolved. Theorganic layer is separated and evaporated to dryness. To an ice cooledsolution of the residue in 25 ml. of pyridine, 2 ml. of ethylchloroformate is added dropwise. After about 5 hours in the cold themixture is poured onto ice: water. The precipitated solid isrecrystallized from Skellysolve B to give 2.9 g. (83%) of ethylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], melting at 70° to 73°C.

EXAMPLE 41B

Ethyl 5'-methylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]

A solution of the amine free base prepared from 1.97 g. (0.00785 M) of5'-methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](obtained as in Example 34B), in 16 ml. of pyridine, is cooled in an icebath. After the addition of 1.25 ml. of ethyl chloroformate the mixtureis allowed to stand in the cold for about 5.5 hours and then poured intoice water. The gum that precipitates is extracted with ether. Thecombined extracts are washed successively with water, ice cold 2.5 Nhydrochloric acid, water, aqueous sodium bicarbonate solution and brine,and evaporated to dryness. The residue is chromatographed over a 250 ml.column of silica gel with elution by 5% ethyl acetate: methylenechloride. The fractions shown alike by TLC are combined to give 2.19 g.of ethyl 5'-methylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],having a melting point of 55° to 60.5° C.

EXAMPLE 42B

Ethyl 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]

To an ice cooled solution of the amine free base prepared from 2.38 g.(0.00926 M) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)] (obtained as in Example 35B), in 0.82 ml. oftriethylamine and 40 ml. of tetrahydrofuran, 0.87 ml. of ethylchloroformate is added. The mixture is kept in the cold for about 6hours and then evaporated to dryness under vacuum. The residue isdissolved in water and ether and the organic layer washed with water andbrine and then evaporated to dryness. The residue is chromatographed ona 250 ml. column of silica gel with elution by 10% acetone: SkellysolveB. The fractions shown alike by TLC are combined to yield 2.22 g. (79%)of ethyl 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] as awaxy solid.

Following the procedures of Examples 40B through 42B but substitutinganother spiro(cyclohexane-1,2'-indan -4-amine[I(b)] and another loweralkyl haloformate, such as

1. 5'-chlorospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]and methyl chloroformate,

2. 4'-ethylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] andpropyl chloroformate, and the like,

yields, respectively,

1. methyl 5'-chlorospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],

2. propyl 4'-ethylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], andthe like.

EXAMPLE 43B

Spiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)]

A solution of 2.9 g. (0.0106 M) of ethylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared in Example40B) in 50 ml. of tetrahydrofuran, is added to a well stirred suspensionof 0.5 g. of lithium aluminum hydride in 25 ml. of tetrahydrofuran. Themixture is heated at reflux for about 6 hours and then cooled in ice.There is added successively 0.5 ml. of water, 0.5 ml. of 15% aqueoussodium hydroxide solution and 1.5 ml. of water. The inorganic gel iscollected on a filter and the filtrate evaporated to dryness. An ethersolution of the residue is treated with 6 N hydrochloric acid to give1.8 g. (66%) of spiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)], melting at 251° to 254° C.

Anal. Calcd. for C₁₅ H₂₂ ClN.1/3H₂ O: C, 69.88; H, 9.22; N, 5.43.

Found: C, 69.99; H. 8.55; N, 5.25.

EXAMPLE 44B

5'-Methylspiro(cyclohexane-1,2'-indan)-4-methylamine[I(b)]

To a well stirred suspension of 0.33 g. of lithium aluminum hydride in 8ml. of tetrahydrofuran, a solution of 2.19 g. (0.00764 M) of ethyl5'-methylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared inExample 41B) in 50 ml. of tetrahydrofuran is added. The mixture isstirred at room temperature for about 6 hours. After cooling in an icebath, there is added successively 0.33 ml. of water, 0.33 ml. of 15%sodium hydroxide solution and 0.99 ml. of water. The resulting inorganicgel is collected on a filter, rinsed well with ether and the filtrateevaporated to dryness. A solution of the residual gum in 35 ml. oftetrahydrofuran is added to a well stirred suspension of 0.33 g. oflithium aluminum hydride in 5 ml. of tetrahydrofuran. After about 6hours of stirring at room temperature the reaction mixture is treated asabove. The residual gum is dissolved in a small amount of ether andextracted 3 times with 20 ml. of 2.5 N hydrochloric acid. The combinedextracts are washed with ether and made basic. The material thatprecipitates is extracted with ether and the extracts evaporated todryness to give5'-methylspiro(cyclohexane-1,2'-indan)-4-methylamine[I(b)] as gum.

EXAMPLE 45B

5'-Methoxyspiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)]

To a well stirred suspendion of 0.32 g. of lithium aluminum hydride in 8ml. of tetrahydrofuran, a solution of 2.22 g. (0.00732 M) of ethyl5'-methoxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared inExample 42B) in 50 ml. of tetrahydrofuran is added. After about 18 hoursof stirring at room temperature the mixture is cooled in an ice bath andthere is added successively 0.32 ml. of water, 0.32 ml. of 15% aqueoussodium hydroxide solution and 96 ml. of water. The resulting precipitateis collected on a filter and the filtrate evaporated to dryness. Asolution of the residue in a small amount of ether is extracted with 2.5N hydrochloric acid. A precipitate suspended in the acid layer isextracted with methylene chloride and evaporated to dryness. The acidportion is made basic, extracted with ether and evaporated to dryness. Asolution of the latter residue in ether is treated with an excess ofethereal hydrochloric acid. A precipitate is collected on a filter,combined with the residue from the methylene chloride extract, andrecrystallized from methanol: ether to give 0.56 g. (35.1% yield) of5'-methoxyspiro(cyclohexane-1,2-indan)-4-methylaminehydrochloride-[I(b)], melting at 225° to 229° C.

Anal. Calcd. for C₁₆ H₂₄ ClNO.1/2CH₃ OH: C, 66.53; H, 8.80; N, 4.70

Found: C, 66.74; H, 8.54; N, 4.82.

Following the procedures of Examples 34B through 45B but substitutinganother lower alkyl spiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] asstarting material, such as

1. ethyl 5'-bromospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],

2. propyl 4'-ethoxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], andthe like,

yields, respectively,

1. 5'-bromospiro(cyclohexane-1,2'-indan)-4-methyl-aminehydrochloride[I(b)],

2. 4'-ethoxyspiro(cyclohexane-1,2'-indan)-4-methyl-aminehydrochloride[I(b)], and the like.

EXAMPLE 46B

4'-Fluoro-4-[methyl[spiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)]

To a suspension of 1 g. (0.0040 M) ofspiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)](prepared as in Example 43B) in 20 ml. of dimethylformamide, 0.17 g. ofsodium hydride is added. After about 1 hour, 0.8 g. of potassium iodide,1.25 g. of potassium carbonate and 1.15 g. of the2,2-dimethyl-1,3-propandiol ketal of 4-chloro-4'-fluorobutyrophenone isadded to the mixture. The mixture is heated in an oil bath at about 110°C. for about 17 hours and allowed to cool. The solvent is then removedunder vacuum and the residue dissolved in benzene and water. The organiclayer is washed with water and brine and evaporated to dryness. Amixture of the residue and 7.5 ml. of 2.5 N hydrochloric acid in 15 ml.of methanol is stirred at room temperature for about 2 hours. Most ofthe methanol is removed under vacuum and the precipitated solidcollected on a filter. This is recrystallized twice from methylenechloride: [ethyl acetate to give 0.77 g] (45%) of4'-fluoro-4-[methyl[spiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)], melting at 195° to 197° C., and also named4'-fluoro-4-[spiro[cyclohexane-1,2'-indan)-4-yl-N-methylamino]butyrophenonehydrochloride.

Anal. Calcd. for C₂₅ H₃₁ ClFNO.1/2H₂ O: C, 70.65; H, 7.35; N, 3.29.

Found: C, 71.10; H, 7.44; N, 3.20.

EXAMPLE 47B

4'-Fluoro-4-[methyl[5'-methylspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)]

A mixture of 0.72 g. (0.00314 M) of5'-methylspiro(cyclohexane-1,2'-indan)-4-methylamine[I(b)] (prepared inExample 44B), 0.99 g. of potassium carbonate, 0.65 g. of potassiumiodide and 0.9 g. of the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-4'-fluorobutyrophenone in 16 ml. of dimethylformamide is heatedin an oil bath at about 90° C. for about 18 hours. Most of the solventis removed under vacuum and the residue dissolved in benzene and water.The organic layer is washed with water and brine and evaporated todryness. The residue is stirred with 12 ml. of methanol and 6 ml. of 2.5N hydrochloric acid for about 3 hours at room temperature. Most of themethanol is removed under vacuum and the residue extracted withmethylene chloride. The extract is washed with N sodium hydroxidesolution and evaporated to dryness. The residue is chromatographed on a200 ml. column of silica gel with elution by 30% Skellysolve B:methylene chloride saturated with ammonium hydroxide. Those fractionsfound alike by TLC are dissolved in methylene chloride. The lattersolution is washed with 2.5 N hydrochloric acid, evaporated to drynessand recrystallized from methanol: ether to yield 0.25 g. (18.5%) of4'-fluoro-4-[methyl[5'-methylspiro[cyclohexane-1,2'-indan]butyrophenonehydrochloride[I(b)], melting at 212.5° to 214° C.

Anal. Calcd. for C₂₆ H₃₃ ClFNO: C, 72.62; H, 7.74; N, 3.26.

Found: C, 72.17; H, 7.79; N, 3.26.

EXAMPLE 48B

4'-Fluoro-4-[methyl[5'-methoxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochoride[I(b)]

A mixture of the amine free base prepared from 0.84 g. (0.0030 M) of5'-methoxyspiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)] (obtained as in Example 45B), 0.95 g. of potassiumcarbonate, 0.62 g. of potassium iodide and 0.86 g. of the2,2-dimethyl-1,3-propane-diol ketal of 4-chloro-4'-fluorobutyrophenonein 15 ml. of dimethylformamide is heated in an oil bath at about 90° C.for about 18 hours. Most of the solvent is removed under vacuum and theresidue dissolved in benzene and water. The organic layer is washed withwater and brine and then evaporated to dryness. A solution of theresidue in 12 ml. of methanol and 6 ml. of 2.5 N hydrochloric acid isstirred at room temperature for about 3 hours. Most of the methanol isremoved under vacuum and the residue extracted with methylene chloride.The residue is washed with N aqueous sodium hydroxide solution andevaporated to dryness. The residue is chromatographed on a 200 ml. ofcolumn of silica gel with elution by 30% Skellysolve B: methylenechloride saturated with ammonium hydroxide. Those fractions found alikeby TLC are pooled and evaporated to dryness. The residue is streakedonto 3 preparative TLC plates and eluted with methylene chloridesaturated with ammonium hydroxide. The band having the strongestultraviolet absorbtion is eluted and evaporated to dryness to give 0.45g. (33.6% yield) ofp-fluoro-4-[methyl]5'-methoxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochlorede[I(b)] as an amorphous foam.

Following the procedures of Example 46B through 48B but substituting thesame and other (a) acid addition salts ofspiro(cyclohexane-1,2'-indan)-4-lower alkylamines [I(b)] and (b) the2,2-dimethyl-1,3-propanediol ketal of ω-haloalkanaryl ketones instoichiometrically appropriate amounts as starting materials, such as

1. spiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] andthe 2,2-dimethyl-1,3-propanediol ketal of3'-bromo-3-chloropropiophenone,

2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-methyl-aminehydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-2'-ethoxybutyrophenone,

3. 5'-propionylamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of5-chloro-4'-propylvalerophenone and the like,

yields, respectively,

1.3'-bromo-3-[methyl[spiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenonehydrochloride[I(b)],

2.2'-ethoxy-4-[methyl[6'-ethylspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)],

3.4'-propyl-5-[methyl[5'-propionylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]valerophenonehydrochloride[I(b)], and the like.

EXAMPLE 49B

1'-Hydroxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17]

A solution of 2.6 g. (0.01 M) ofspiro(cyclohexane-1,2'-indan)-1',4-dione ethylene ketal[9] (prepared asin Example 16B) in 50 ml. of tetrahydrofuran is added to a well stirredsuspension of 0.5 g. of lithium aluminum hydride in 10 ml. oftetrahydrofuran. The mixture is stirred at room temperature for about 5hours, cooled in ice and treated successively with 0.5 ml. of water, 0.5ml. of 15% aqueous sodium hydroxide solution and 1.5 ml. of water. Theinorganic gel is removed by filtration and the filtrate evaporated todryness. The residue is recrystallized from cyclohexane to give 2.45 g.(95%) of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17], having a melting point of 125° to 128° C.

Anal. Calcd. for C₁₆ H₂₀ O₃ : C, 73.82; H, 7.74.

Found: C, 73.48; H, 7.78.

Following the procedure of Example 49B but substituting otherspiro(cyclohexane-1,2'-indan)-1,4-dione alkylene ketals[9] as startingmaterials, such as

5'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione ethylene ketal[9]yields,

1'-hydroxy-5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[17].

EXAMPLE 50B

1'-Acetoxyspiro(cyclohexane-1,2'-indan)-4-one[19]

1. A solution of 2.45 g. (0.0094 M) of1'-hydroxy-spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17](prepared in Example 49B) and 5 ml. of 2.5 N hydrochloric acid in 50 ml.of acetone is allowed to stand for about 17 hours at room temperature.Most of the solvent is removed under vacuum and the residue dissolved inwater and ether. The organic layer is washed with water and brine andevaporated to dryness to give1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one[18], as a gum.

2. A solution of the 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one[18]obtained in (1), above, and 4 ml. of acetic anhydride in 16 ml. ofpyridine is allowed to stand at room temperature for about 7 hours andthen poured into ice:water. The precipitate is extracted with ether.This extract is washed successively with water, ice cold 2.5 Nhydrochloric acid, water and saturated aqueous sodium bicarbonatesolution and then evaporated to dryness. The residual solid isrecrystallized from Skellysolve B to give 1.82 g. (75% yield) of1'-acetoxyspiro(cyclohexane-1,2'-indan)-4-one[19], melting at 87° to 89°C.

Anal. Calcd. for C₁₆ H₁₈ O₃ : C, 74.39; H, 7.02.

Found: C, 73.93; H, 6.95.

Following the procedure of Example 50B but substituting other1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one alkylene ketals[17] and ananhydride of another hydrocarbon carboxylic acid for acetic anhydride,such as

1. 1'-hydroxy-4'-acetylamidospiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[17] and propionic anhydride,

2. 1'-hydroxy-5'-ethylspiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[17] and isopropionic anhydride, and the like,

yields, respectively,

1.1'-propionyloxy-4'-acetylamidospiro(cyclohexane-1,2'-indan)-4-one[19],

2. 1'-isopropionyloxy-5'-ethylspiro(cyclohexane-1,2'-indan)-4-one[19],and the like.

EXAMPLE 51B

1'-Acetoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[21]

1. To a solution of 1.82 g. (0.0071 M) of1'-acetoxy(cyclohexane-1,2'-indan)-4-one[19] (prepared in Example 50B)in 25 of 95% isopropanol, 0.32 g. of sodium borohydride is added.Following about 1 hour of stirring at room tempeerature most of thesolvent is removed under vacuum. The residue is dissolved in ether andwater, the organic layer is washed with water and brine and evaporatedto dryness to give 1'-acetoxyspiro(cyclohexane-1,2'-indan)-4-ol[20].

2. The residual gummy 1'-acetoxyspiro(cyclohexane-1,2'-indan)-4-ol[20]obtained in (1), above, is dissolved in pyridine. This solution iscooled in ice and treated with 1.7 ml. of methanesulfonyl chloride.After standing in the cold for about 17 hours the mixture is poured intoice and water. The gum that precipitates is extracted with ether. Theorganic layer is washed successively with water, 2.5 N hydrochloricacid, water and brine and evaporated to dryness. The residue isrecrystallized twice from a mixture of ether and petroleum ether to give1.54 g. (65% yield) of 1'-acetoxyspiro(cyclohexane-1,2'-indan-4-olmethanesulfonate[21] having a melting point of 97° to 100° C.

Anal. Calcd. for C₁₇ H₂₀ O₅ S: C, 60.69; H, 5.99; M.W. 338.

Found: C, 60.60; H, 6.58; m/e 338.

Following the procedure of Example 51B but substituting other1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ones[19] and other loweralkylsulfonyl halides, such as

1. 1'-propionyloxy-5'-chlorospiro(cyclohexane-1,2'-indan)-4-one[19] andethanesulfonyl bromide,

2. 1'-butyroyloxy-7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-one[19] andbutanesulfonyl chloride, and the like,

yields respectively.

1. 1'-propionyloxy-5'-chlorospiro(cyclohexane-1,2'-indan)-4-olethanesulfonate[21],

2. 1'-butyryloxy-7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-olbutanesulfonate[21], and the like.

EXAMPLE 52B

1'-Hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)]; also named4-aminospiro(cyclohexane-1,2'-indan)-1'-ol[I(b)]

A mixture of 5 g. (0.015 M) of1'-acetoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[21](obtained as in Example 51B) and 5 g. of sodium azide in 50 ml. ofdimethylformamide is stirred for about 17 hours in an oil bath at about90° C. The solvent is then removed under vacuum and the residuedissolved in benzene and water. The organic layer is washed with waterand brine and then evaporated to dryness to give1'-acetoxyspiro(cyclohexane1,2'-indan)-4-ylazide[22].

A solution of the crude azide[22] in 80 ml. of tetrahydrofuran is addedto 1.2 g. of lithium aluminum hydride in 20 ml. of tetrahydrofuran.After about 4.5 hours of stirring at room temperature the mixture iscooled in ice and treated successively with 1.2 ml. of water, 1.2 ml. of15% aqueous sodium hydroxide solution and 3.6 ml. of water. Theinorganic gel is collected on a filter and the filtrate evaporated todryness. The residue is recrystallized from a small amount of ethylacetate to give 1.71 g. (53% of theoretical yield) of1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)], melting at 156°to 160° C. the analytical sample melts at 158° to 161° C.

Anal. Calcd. for C₁₄ H₁₉ NO: C, 77.38; H, 8.81; N, 6.45.

Found: C, 76.98; H, 8.79; N, 6.41.

Extracting the thus obtained free base form of the compound with etherand treating the extract with the an ethereal solution of a suitableacid (e.g., hydrochloric), gives the corresponding acid addition saltform of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)].

Following the procedure of Example 52B but substituting other1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonates[21]as starting mateials, such as

1. 1'-acetoxy-4'-ethylspiro(cyclohexane-1,2'-indan)-4-olpropanesulfonate[21],

2. 1'-propionyloxy-5'-fluorospiro(cyclohexane-1,2'-indan)-4-olethanesulfonate[21], and the like,

yields, respectively,

1. 1'-hydroxy-4'-ethylspiro(cyclohexane-1,2'-indan)-4-amine[I(b)],

2. 1'-hydroxy-5'-fluorospiro(cyclohexane-1,2'-indan)-4-amine[I(b)], andthe like.

EXAMPLE 53B

4'-Fluoro-4-[[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)]

A mixture of 1.71 g. (0.0079 M) of1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)] (prepared inExample 51B), 1.58 g. of potassium iodide, 4.25 g. of potassiumcarbonate and 2.28 g. of the 2,2-dimethyl-1,3-propanediol of4-chloro-p-fluorobutyrophenone in 40 ml. of dimethylformamide is stirredfor about 17 hours in an oil bath at about 90° C. The solvent is thenremoved under vacuum and the residue partitioned between water andbenzene. The organic layer is washed with water and brine and evaporatedto dryness. A mixture of the residue and 7.5 ml. of 2.5 N hydrochloricacid in 15 ml. of methanol is stirred at room temperature for about 4hours. Most of the methanol is removed under vacuum and the precipitatedsolid collected on a filter. This material is recrystallized to give1.03 g. (33% yield) of4'-fluoro-4-[[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)], having a melting point of 190° to 193° C.

Anal. Calcd. for C₂₄ H₂₉ ClFNO₂ : C, 68.97; H, 6.99 N, 3.35.

Found: C, 69.37; H, 7.77 N, 3.11.

Following the procedure of Example 53B but substituting the same andother (a) 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and (b)the 2,2-dimethyl-1,3-propanediol ketals of ω-haloalkanaryl ketones instoichiometrically appropriate amounts as starting materials, such as

1. 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)] and the2,2-dimethyl-1,3-propanediol ketal of 2-bromo-4-ethylpropiophenone,

2. 1'-hydroxy-7'-fluorospiro(cyclohexane-1,2'-indan)-4-amine[I(b)] andthe 2,2-dimethyl-1,3-propanediol ketal of 3',4-dichlorobutyrophenone,

3. 1'-hydroxy-6'-ethoxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)] andthe 2,2-dimethyl-1,3-propanediol ketal of4-chloro-3-ethoxybutyrophenone, and the like,

yields, respectively,

1.4'-ethyl-3-[[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenonehydrochloride[I(b)],

2.3'-chloro-4-[[7'-fluoro-1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride-[I(b)],

3.3'-ethoxy-4-[[6'-ethoxy-1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)], and the like.

EXAMPLE 54B

Ethyl 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]

A suspension of 3.5 g. of1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](obtained as in the paragraph immediately following Example 52B) in 65ml. of methylene chloride is shaken with 50 ml. of N sodium hydroxidesolution until the solid is completely dissolved. The organic layer isseparated and evaporated to dryness. To an ice cooled solution of theresidue in 25 ml. of pyridine, 2 ml. of ethyl chloroformate is addeddropwise. After about 5 hours in the cold the mixture is poured into iceand water. The precipitated solid is recrystallized from Skellysolve Bto give ethyl 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-carbamate(I(b)].

EXAMPLE 55B

1'-Hydroxyspiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)]

A solution of 3 g. of ethyl1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared asin Example 54B) in 50 ml. of tetrahydrofuran, is added to a well stirredsuspension of 0.5 g. of lithium aluminum hydride in 25 ml. oftetrahydrofuran. The mixture is heated at reflux for about 6 hours andthen cooled in ice. There is added successively 0.5 ml. of water, 0.5ml. of 15% aqueous sodium hydroxide solution and 1.5 ml. of water. Theinorganic gel is separated by filtration and the filtrate evaporated todryness. An ether solution of the residue is treated with 6 Nhydrochloric acid to give1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)].

EXAMPLE 56B

1-[1'-Hydroxyspiro(cyclohexane-1,2'-indan)-4-yl]piperidinehydrochloride[I(b)]

Following the procedure of Example 36B but substituting astoichiometrically appropriate amount of1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](prepared as in the first paragraph following Example 52B) as startingmaterial, yields1-[1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-yl]piperidinehydrochloride[I(b)].

Following the procedure of Example 56B but substituting other1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine acid additionsalts[I(b)] and other dihaloalkanes in stoichiometrically appropriateamounts as starting materials, such as

1. 5'-chloro-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)] and 1,6-diiodohexane,

2. 1'-hydroxy-4'-propoxyspiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)] and 1,4-dibromobutane, and the like,

yields, respectively,

1.1-[5'-chloro-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneiminehydrochloride[I(b)],

2.1-[1'-hydroxy-4'-propoxyspiro(cyclohexane-1,2'-indan)-4-yl]pyrrolidinehydrochloride[I(b)], and the like.

EXAMPLE 57B

4'-fluoro-4-[methyl[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)]

Following the procedure of Examples 46B through 48B but substituting astoichiometrically appropriate amount of1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)] (prepared as in Example 55B) as starting material,yields4'-fluoro-4-[methyl[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)].

Following the procedure of Example 57B but substituting other1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-lower alkylamines[I(b)] andthe 2,2-dimethyl-1,3-propanediol ketals of ω-haloalkanaryl ketones instoichiometrically appropriate amounts as starting materials, such as

4'-ethoxy-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-propylaminehydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-3'-ethylbutyrophenone, yields,

3'-ethyl-4-[propyl[4'-ethoxy-1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)].

EXAMPLE 58B

1'-Chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23]

A solution of 6.5 g. (0.025 M) of1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17](prepared as in Example 49B) in 86 ml. of tetrahydrofuran is cooled inice: methanol. To this there is added dropwise 15.6 ml. of 1.64 N butyllithium in pentane, and after about 5 minutes, 2.04 ml. (3.03 g.) ofmethane sulfonyl chloride in 43 ml. of tetrahydrofuran. After standingfor about 4 hours in the cold, the solvent is removed under vacuum. Theresidue is treated with ether and the inorganic solid collected on afilter. The filtrate is evaporated to dryness and the residuerecrystallized from petroleum ether to give 6.06 g. (87%) of1'-chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23], havinga melting point of 103.5 to 108° C.

Anal. Calcd. for C₁₆ H₁₉ ClO₂ : Calcd. M.W. 278.

Found: m/e 278.

Following the procedure of Example 58B but substituting other1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketals and otherlower alkyl sulfonyl halides, such as

1. 1'-hydroxy-4'-chlorospiro(cyclohexane-1,2'indan)-4-one ethyleneketal[17] and ethane sulfonyl bromide,

2. 1'-hydroxy-6'-propoxyspiro(cyclohexane-1,2'indan)-4-one ethyleneketal[17] and ethane sulfonyl chloride, and the like,

yields, respectively,

1. 1'-bromo-4'-chlorospiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[23],

2. 1'-chloro-6'-propoxyspiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[23], and the like.

EXAMPLE 59B

1'-Aminospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24]

A mixture of 3.5 g. (0.013 M) of1'-chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23](prepared as in Example 58B) and 3.5 g. of sodium azide indimethylformamide is stirred in an oil bath at about 90° C. for about 17hours. The solvent is removed under vacuum and the solid dissolved inbenzene and water. The organic layer is washed with water and brine andevaporated to dryness. A solution of the residue in 60 ml. oftetrahydrofuran is added to 0.5 g. of lithium aluminum hydride in 10 ml.of tetrahydrofuran. After standing for about 4.5 hours the mixture iscooled in ice and treated successively with 0.5 ml. of water, 0.5 ml. of15% aqueous sodium hydroxide solution and 1.5 ml. of water. Theinorganic gel is collected on a filter and the filtrate evaporated todryness. The residual gum is dissolved in ether and treated with 5 Nhydrochloric acid in ether, to give 2.42 g. (81% yield) of1'-aminospiro(cyclohexane1,2'-indan)-4-one ethylene ketal[24], having amelting point of 224° to 227° C.

Anal. Calcd. for C₁₆ H₂₂ ClNO₂ : M.W. 259

Found: m/e 259.

Following the procedure of Example 59B but substituting other1'-halospiro(cyclohexane-1,2'-indan)-4-one ethylene ketals[23] asstarting materials, such as

1. 1'-bromo-5'-fluorospiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[23],

2. 1'-chloro-6'-nitrospiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[23], and the like,

yields, respectively,

1. 1'-amino-5'-fluorospiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[24],

2. 1'-amino-6'-nitrospiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[24], and the like.

EXAMPLE 60B

1'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[26]

1. A solution of 7 g. of 1'-aminospiro(cyclohexane-1,2'-indan)-4-oneethylene ketal[24] (prepared as in Example 59B) and 30 ml. of aceticanhydride in 60 ml. of pyridine is allowed to stand at room temperaturefor about 5 hours. The mixture is poured into ice: water and theprecipitated gum extracted with ether. The organic layer is washedsuccessively with watere, 2.5 N hydrochloric acid and brine andevaporated to dryness to give1'-acetamidospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[25].

2. The residual 1'-acetamidospiro(cyclohexane-1,2'indan)-4-one ethyleneketal[25], obtained in (1), above, and 10 ml. of 2.5 N hydrochloric acidare dissolved in 100 ml. acetone. After about 20 hours at roomtemperature most of the solvent is removed under vacuum. The residue isdissolved in methylene chloride and water. The organic layer is washedwith water and brine and evaporated to dryness. The residual gum ischromatographed on a 600 ml. column of silica gel with elution by 25%acetone in methylene chloride. The crystalline fractions are eluted withethyl acetate: cyclohexane to give 3.81 g. of1'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[26], having a meltingpoint of 113° to 116° C.

Following the procedure of Example 60B but substituting another1'-aminospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24] andanother anhydride of a hydrocarbon carboxylic acid, such as

1. 1'-amino-4'-ethylspiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[24] and propionic anhydride,

2. 1'-amino-6'-propoxyspiro(cyclohexane-1,2'-indan)-4-one ethyleneketal[24] and isopropionic anhydride, and the like,

yields, respectively,

1. 4'-ethyl-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-one [26],

2.1'-isopropionylamido-6'-propoxyspiro(cyclohexane-1,2'-indan)-4-one[26],and the like.

EXAMPLE 61B

1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-ols[27]

To 3.81 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[26](prepared in Example 60B) in 100 ml. of isopropanol, 0.6 g. of sodiumborohydride is added. After about 5 hours most of the solvent is removedunder vacuum and the residue suspended in water. The resulting solid iscollected on a filter and recrystallized from aqueous methanol. There isobtained first 0.9 g. (24% yield) of1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol(isomer A)-[27], having amelting point of 247° to 250° C.

Anal. Calcd. for C₁₆ H₂₁ NO₂ : C, 74.10; H, 8.16; N, 5.40.

Found: C, 73.70; H, 8.19; N, 5.01.

On standing, there is obtained from the mother liquors 1.21 g. (32%) of1'-acetamidospiro(cyclohexane1,2'-indan)-4-ol (isomer B)[27], having amelting point of 184° to 186° C.

Anal. Found: C, 73.91; H, 8.23; N, 5.30.

Following the procedure of Example 61B but substituting other1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ones[26], such as

1. 1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-one[26],

2.1'-isopropionylamido-5'-propylspiro(cyclohexane-1,2'-indan)-4-one[26],and the like,

yields, respectively,

1. 1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-ols[27],

2.1'-isopropionylamido-5'-propylspiro(cyclohexane-1,2'-indan)-4-ols[27],and the like.

EXAMPLE 62B

1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate (isomerA)[28]

A mixture of 0.9 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan-4-ol(isomer A) [27] (prepared in Example 61B) in 20 ml. of pyridine iswarmed until all the solid has dissolved. There is then added 1 ml. ofmethane sulfonyl chloride. Follwoing about 4 hours of standing at roomtemperature, most of the solvent is removed under vacuum. The residue isthen dissolved in water and methylene chloride, and the organic layerwashed successively with water, 2.5 N hydrochloric acid, water andbrine. The solution is evaporated to dryness and the residuerecrystallized from acetone: Skellysolve B to give 0.72 g. of1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate (isomerA)[28], having a melting point of 137° to 139° C.

Anal. Calcd. for C₁₇ H₂₃ NO₄ S: C, 60.51; H, 6,87; N, 4.15.

Found: C, 60.10; H, 6.85; N, 4.00.

EXAMPLE 63B

1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate (isomerB) [28]

To an ice cold solution of 1.21 g. of1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol (isomer B) [27 ](prepared in Example 61B) in 12 ml. of pyridine, 1.2 ml. of methanesulfonyl chloride is added. After about 5 hours in the cold the mixtureis poured into ice: water. The solid that precipitates is recrystallizedfrom acetone: Skellysolve B to give 1.21 g. of1'-acetamidospiro(cyclohexane-1,2'-indan-4-ol methanesulfonate (isomerB) [28], melting at 161° to 163° C.

Anal. Calcd. for C₁₇ H₂₃ NO₄ S: C, 60.61; H, 6.87; N, 4.15; M.W. 337.

Found: C, 60.40; H, 6.97; N, 4.21; m/e 337.

Following the procedures of Examples 62B and 63but substituting other1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ols[27], such as

1'-propionylamido-5'-propoxyspiro(cyclohexane-1,2'-indan)-4-ol (isomerA) [27],

yields,

1'-propionylamido-5'-propoxyspiro(cyclohexane-1,2'-indan)-4-olmethanesulfonate (isomer A)[28].

EXAMPLE 64B

1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]

Following the procedure of Example 33B but substituting1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[28](prepared as in Examples 62B or 63B) as starting material, yields1'-acetomidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)].

Following the procedure of Example 64B but substituting other1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonates[28]as starting materials, such as

1. 1'-acetamido-4'-ethoxyspiro(cyclohexane-1,2'-indan)-4-olethanesulfonate[28],

2. 1'-isopropionylamido-5'-fluorospiro(cyclohexane-1,2'-indan)-4-olpropanesulfonate[28], and the like,

yields, respectively,

1. 1'-acetamido-4'-ethoxyspiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)],

2. 1'-isopropionylamido-5'-fluorospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)], and the like.

EXAMPLE 65B

1'-Acetamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidinehydrochloride[I(b)]

Following the procedure of Example 36B but substituting1'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](prepared as in Example 64B) as starting material, yields1'-acetamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidinehydrochloride[I(b)].

Following the procedure of Example 65B but substituting other1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amine acid addition salts[I(b)] and other dihaloalkanes in stoichiometrically appropriate amountsas starting materials, such as

1. 1'-acetamido-7'-ethylspiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)]and 1,4-dibromobutane,

2. 5'-amino-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)] and 1,5-diiodopentane, and the like,

yields, respectively,

1. 1'-acetamido-1-[7'-ethylspiro(cyclohexane-1,2'-indan)-4-yl]pyrrolidine hydrochloride[I(b)], 2.1-[5'-amino-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-yl]piperidinehydrochloride [I(b)], and the like.

EXAMPLE 66B

4'-fluoro-4-[[1'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]

Following the procedure of Example 37B but substituting1'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](prepared as in Example 64B) as starting material, yields4'-fluoro-4[[1'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I-(b)].

Following the procedure of Example 66B but substituting acid additionsalts of other 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines[I(b)]and other ω-haloalkanaryl ketones in stoichiometrically appropriateamounts, such as

1. 4'-chloro-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of3-chloro-4'-methyl propiophenone,

2. 5'-ethyl-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)]and the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-3'-ethoxybutyrophenone, and the like,

yields, respectively,

1.4'-methyl-3-[[4'chloro-1'-propionylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenonehydrochloride[I(b)],

2.3'-ethoxy14-[[5'-ethyl-1'-isopropionylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)], and the like.

EXAMPLE 67B

Ethyl 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]

Following the procedures of Example 40B through 42B but substituting1'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](prepared as in Example 64B) as starting material, yields ethyl1'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)].

Following the procedure of Example 67B but substituting acid additionsalts of other 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines andother lower alkyl haloformates as starting materials, such as

1. 5'-bromo-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride [I(b)] and propyl chloroformate,

2. 4'-amino-1'-isopropionylamidospiro(cyclohexane-1,2'indan)-4-aminehydrochloride[I(b)] and butyl chloroformate, and the like,

yields, respectively,

1. propyl5'-bromo-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],

2. butyl4'-amino-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],and the like.

EXAMPLE 68B

1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)]

Following the procedure of Example 43B but substituting ethyl1'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared asin Example 67B) as starting material, yields1'-acetamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)].

Following the procedure of Example 68B but substituting other loweralkyl 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-carbamates[I(b)] asstarting materials, such as

1. propyl4'-chloro-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]

2. butyl5'-ethylamino-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],and the like,

yields, respectively,

1.4'-chloro-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)],

2.5'-ethylamino-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)], and the like.

EXAMPLE 69B

4'-fluoro-4[methyl[1'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)]

Following the procedure of Example 46B but substituting1'-acetamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)] (prepared as in Example 68B) as starting material,yields4'-fluoro-4[methyl[1'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)].

Following the procedure of Example 69B but substituting acid additionsalts of other 1'-acylamidospiro[cyclohexane-1,2'-indan)-4-loweralkylamines[I(b)] and the 2,2-dimethyl-1,3-propanediol ketals of otherω-haloalkanaryl ketones in stoichiometrically appropriate amounts asstarting materials, such as

1.6'-ethoxy-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of3'-bromo-3-chloropropiophenone,

2.5'-amino-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of5-chloro-2'-propoxyvalerophenone, and the like,

yields, respectively,

1.3'-bromo-3-[methyl[6'-ethoxy-1'-propionylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenonehydrochloride[I(b)],

2.2'-propoxy-5-[methyl[5'-amino-1'-isopropionyl-amidospiro[cyclohexane-1,2'-indan]-4-yl]amino]valerophenonehydrochloride[I(b)], and the like.

EXAMPLE 70B

5'-Nitrospiro(cyclohexane-1,2'-indan)-4-one[29]

To an ice cooled solution of 9.04 g. (0.045 M) ofspiro(cyclohexane-1,2'-indan)-4-one[11] [prepared as in (a) of Example24B] in 45 ml. of trifluoroacetic acid, 9 ml. of nitric acid is added.After reaction in the cold for about 2 hours, the solution is pouredonto ice: water. The precipitated solid is chromatographed on 1 l. ofsilica gel and eluted with 25% acetone: Skellysolve B. The crystallinefractions obtained are combined and recrystallized from acetone:Skellysolve B to give 7.23 g. (65% yield) of5'-nitrospiro(cyclohexane-1,2'-indan)-4-one[29] having a melting pointof 124° to 128° C. The analytical sample melted at 126° to 127.5° C.

Anal. Calcd. for C₁₄ H₁₅ NO₃ : C, 68.55; H, 6.16; N, 5.71.

Found: C, 68.38; H, 6.24; N, 5.95.

EXAMPLE 71B

5'-Acetamidospiro(cyclohexane-1,2'-indan)-4-one[31]

1. A suspension of 0.5 g. of palladium on carbon catalyst in a solutionof 7.89 g. (0.32 M) of 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one[29](obtained as in Example 70B) in 150 ml. of ethyl acetate is shaken underhydrogen. After about 3 hours of shaking an additional 0.5 g. of thesame catalyst is added and shaking continued. When the theoreticaluptake of hydrogen is observed, the catalyst is removed by filtrationand a solution of 6.1 g. of p-toluenesulfonic acid in a small volume ofmethanol is added. The solvent is removed under vacuum andrecrystallization from methanol: acetone attempted, but the ocurrence,on standing in the cold for about 65 hours, of extensive decomposition,is apparent. The material is converted to the free base,5'-aminospiro(cyclohexane-1,2'indan)-4-one[30] .

2. A solution of the product [30], obtained in (1), above, in 40 ml. ofpyridine is treated with 10 ml. of acetic anhydride. After about 5 hoursthe mixture is poured onto ice: water and the resulting precipitateextracted with methylene chloride. This solution is washed successivelywith water, 2.5 N hydrochloric acid, water and brine and then evaporatedto dryness. The residue is chromatographed on a column of 700 ml. ofsilica and eluted with 25% acetone: methylene chloride. The crystallinefractions are combined and recrystallized from methanol to give 3.15 g.(38%) of 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[31], melting at169° to 171° C.

Anal. Calcd. for C₁₆ H₁₉ NO₂ : C, 74.68; H, 7.44; N, 5.44; M.W. 257 .

Found: C, 74.36; H, 7.54; N, 5.48; m/e 257.

Following the procedure of Example 71B but substituting other5'-nitrospiro(cyclohexane-1,2'-indan)-4-one-[29] and other anhydrides ofhydrocarbon carboxylic acids as starting materials, such as

6'-ethoxy-5'-nitrospiro(cyclohexane-1,2'-indan)-4-one[29]and propionicanhydride, yields,

6'-ethoxy-5'-propionamidospiro(cyclohexane-1,2'indan)-4-one[31] .

EXAMPLE 72B

5'-Acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[33]

1. To 3.15 g. (0.012 M) of5'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[31] (obtained in Example71B) dissolved in 50 ml. of 95% isopropanol with warming on a steambath, 0.5 g. of sodium borohydride is added. After about 4 hours ofstanding at room temperature, the solvent is removed under vacuum. Theresidue is dissolved in methylene chloride and water. The organic layeris washed with water and brine and then evaporated to dryness to give3.03 g. of 5'-acetamidospiro(cyclohexane-1,2'-indan4-ol[32], having amelting point of 148° to 152° C.

2. A solution of the product [32], obtained in (1), above, in 30 ml. ofpyridine is cooled in ice and 3 ml. methanesulfonyl chloride added.After about 5 hours in the cold, the mixture is poured onto ice: waterand extracted with methylene chloride. The solution is washedsuccessively with water, 2.5 N hydrochloric acid, water and brine andevaporated to dryness. The residue is chromatographed on a column of 300ml. of Florisil and eluted with 25% acetone: Skellysolve B. Thecrystalline fractions are combined and recrystallized from ethylacetate: cyclohexane. There is obtained 1 g. (25%) of5'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[33]having a melting point of 145° to 147° C., and a second crop of 0.2 g.(5%) melting at 143° to 145° C.

Anal. Calcd. for C₁₇ H₂₃ NO₄ S: C, 60.51; H, 6.87; N, 4.15.

Found: C, 60.52; H, 7.00; N, 4.10.

Following the procedure of Example 72B but substituting other5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ones[31], such as

4'-fluoro-5'-propionamidospiro(cyclohexane-1,2'indan)-4-one[31],

yields,

4'-fluoro-5'-propionamidospiro(cyclohexane-1,2'indan-4-olmethanesulfonate[33].

EXAMPLE 73B

5'-Acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]

1. A mixture of 1.2 g. (0.0036 M) of5'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[33](obtained in Example 72B) and 1.2 g. of sodium azide in 10 ml. ofdimethylformamide is stirred for about 20 hours in an oil bath at about90° C. The solvent is then removed under vacuum and the residuepartitioned between water and benzene. The organic layer is washed withwater and brine and then evaporated to dryness to give5'-acetamidospiro(cyclohexane-1,2'-indan)-41ylazide[34].

2. A solution of the residue[34], obtained in (1), above, in 150 ml. ofethyl acetate is shaken under hydrogen in the presence of 0.15 g. of 10%palladium on carbon catalyst. the catalyst is collected on a filter andthe filtrate evaporated to dryness. The residue is dissolved in methanoland treated with 6 N hydrochloric acid in ether. This solution isevaporated to dryness and recrystallized from methanol: ethyl acetate,to give 0.67 g. (63% yield) of5'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)],also named N-[4-aminospiro[cyclohexane1,2'-indan]-5'-yl]acetamidehydrochloride, melting at 270° to 275° C. (with decomposition).

Anal. Calcd. for C₁₆ H₂₃ ClN₂ O.1/2H₂ O: C, 63.24; H, 7.96; N, 9.22;M.W. (free base) 258.

Found: C, 62.80; H, 8.04; N, 8.72; m/e 258.

Following the procedure of Example 73B but substituting other5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonates[33] asstarting materials, such as

1. 6'-ethyl-5'-propionamidospiro(cyclohexane-1,2'indan)-4-olmethanesulfonate[33],

2. 7'-bromo-5'-isopropionamidospiro(cyclohexane1,2'-indan)-4-olmethanesulfonate[33], and the like,

yields, respectively,

1. 6'-ethyl-5'-propionamidospiro(cyclohexane-1,2'indan)-4-aminehydrochloride[I(b)],

2. 7'-bromo-5'-isopropionamidospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)], and the like.

EXAMPLE 74B

5'-Acetamido-1-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidinehydrochloride[I(b)]

Following the procedure of Example 36B but substituting5'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](prepared as in Example 73B) as starting material, yields5'-acetamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidinehydrochloride[I(b)].

Following the procedure of Example 74B but substituting other5'-acylamido(cyclohexane-1,2'-indan)-4-amine acid addition salts[I(b)]and other dihaloalkanes in stoichiometrically appropriate amounts asstarting materials, such as

5'-acetamido-7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)] and 1,4-diiodobutane, and the like,

yields,

5'-acetamido-1-[7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-yl]pyrrolidinehydrochloride[I(b)], and the like.

EXAMPLE 75B

4'-Fluoro-4-[[5'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b) ]

Following the procedure of Example 37B but substituting5'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)](prepared as in Example 73B) as starting material, yields4'-fluoro-4-[[5'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride [I(b)].

Following the procedure of Example 75B but substituting acid additionsalts of other 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines[I(b)]and other ω-haloalkanaryl ketones in stoichiometrically appropriateamounts, such as

6'-ethyl-5'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-3'-ethoxybutyrophenone,

yields,

3'-ethoxy-4-[[6'-ethyl-5'-isopropionylamidospiro[cyclohexane-1,2'-indan]4-yl]amino]butyrophenonehydrochloride[I(b)].

EXAMPLE 76B

Ethyl 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]

Following the procedure of Example 40B but substituting5'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[1(b)](prepared as in Example 73B) as starting material, yields ethyl5'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[1(b)].

Following the procedure of Example 76B but substituting acid additionsalts of other 5'-acylamidospiro(cyclohdexane-1,2'-indan)-4-amines andother lower alkyl haloformates as starting materials, such as

4'-propyl-5'-propionylamidospiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)]and propyl chloroformate,

yields,

propyl4'-propyl-5'-propionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)].

EXAMPLE 77B

5'-Acetamidospiro(cyclohexane-1,2'indan)-4-methylaminehydrochloride[I(b)]

Following the procedure of Example 43B but substituting ethyl5'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate [I(b) ] (preparedas in Example 76B) as starting material, gives5'-acetamidospiro(cyclohexane-1,2'-indan)4-methylaminehydrochloride[I(b) ].

Following the procedure of Example 77B but substituting other loweralkyl 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-carbamates[I(b)] asstarting materials, such as

butyl7'-ethoxy-5'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],and the like,

yields,

7'-ethoxy-5'-isopropionylamidospiro(cyclohexane1,2'-indan)-4-propylaminehydrochloride[I(b)], and the like.

EXAMPLE 78B

4'-Fluoro-4-[methyl[5'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenonehydrochloride[I(b)]

Following the procedure of Example 46B but substituting5'-acetamidospiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride[I(b)] (prepared as in Example 77B) as starting material,yields4'-fluoro-4-[methyl[5'-acetamidospiro[cyclohexane-1,2'-indan]4-yl]amino]butyrophenonehydrochloride [I(b)].

EXAMPLE 79B

4-hydroxy-α-methylspiro(cyclohexane-1,2'-indan)-4-acetic acid[36]

1. A chip of iodine is added to a well stirred mixture of 5.87 g. (0.029M) of spiro(cyclohexane-1,2'-indan)-4-one [11] ]prepared as in (1) ofExample 24B], 6 g. of the known compound methyl α-bromopropionate and 4g. of zinc wool, and the reaction started by heating the mixture ofreflux. After about 6 hours the mixture is allowed to cool, the excessmetal separated on a filter, and the filtrate washed successively with2.5 N hydrochloric acid, water and brine and then evaporated to dryness.The residue is chromatographed on a column of 800 ml. of silica gel andeluted with 5% acetone: Skellysolve B. The fractions similar by thinlayer chromatography are combined to give4-hydroxy-α-methylspiro(cyclohexane-1,2'-indan)-4-acetate[35] as an oil.

2. A mixture of the oily ester [35], obtained in (1), above, 10 ml. of50% aqueous sodium hydroxide solution and 10 ml. of water in 100 ml. ofmethanol, is stirred with heating at reflux for about 17 hours. Thesolvent is then removed under vacuum. A suspension of the residue inwater and ether is made strongly acidic, the organic layer washed withbrine and water and then evaporated to dryness. The residual solid isrecrystallized from ether: Skellysolve B to give 3.98 g. (50%) of4-hydroxy-α-methylspiro(cyclohexane-1,2'-indan)-4-acetic acid-[36],melting at 111° to 114° C.

Anal. Calcd. for C₁₇ H₂₂ O₃ : C, 74.48; H, 8.30.

Found: C, 74.42; H, 8.08. EXAMPLE 80B Sprio(cyclohexane-1,240-indan)-Δ⁴,.sup.α -acetic acid[38]

1. To 4.02 g. of triethylphosphono acetate in 50 ml. of tetrahydrofuran,0.84 g. of 56% sodium hydride (in mineral oil) is added. After about 10minutes, 3.59 g. (0.018 M) of spiro(cyclohexane-1,2-'-indan)-4-one[11][prepared as in (1) of Example 24B] in 50 ml. of tetrahydrofuran, isadded. The mixture is heated at reflux for about 3 hours and allowed tocool. After standing at room temperature for about 17 hours, 100 ml. of2.5 N hydrochloric acid is added. The organic layer is separated, washedwith water and brine and evaporated to dryness to givespiro(cyclohexane-1,2'-indan)-Δ⁴,.sup.α -acetate [37].

2. A mixture of the residual gum [36], obtained in (1), above, 6 ml. of50% aqueous sodium hydroxide solution and 10 ml. of water in 100 ml. ofmethanol is heated at reflux for about 5 hours. The methanol is thenremoved under vacuum, the resulting residue diluted with water andacidified, and the precipitate that forms extracted with ether. Theorganic layer is washed with water and brine and evaporated to dryness.The residue is recrystallized twice from acetone: Skellysolve B to give2.67 g. (61% yield) of spiro(cyclohexane-1,2'-indan)-Δ⁴,.sup.α -aceticacid[38], melting at 119° to 121° C.

Anal. Calcd. for C₁₆ H₁₈ O₂ : C, 79.31; H, 7.49.

Found: C, 79.38; H, 7.70.

EXAMPLE 81B

spiro(cyclohexane-1,2'-indan)acetic acid[39] A mixture of 1.67 g.(0.0069 M) of spiro(cyclohexane-1,2'-indan)-Δ⁴,.sup.α -acetic acid [38](prepared as in Example 80B) and 0.15 g. of Adams catalyst is shakenunder hydrogen until the theoretical uptake is observed (about 25hours). The catalyst is removed by filtration and the filtrateevaporated to dryness. The residue is recrystallized from ether:Skellysolve B to give 1.48 g. (88%) ofspiro(cyclohexane11,2'-indan)acetic acid[39] having a melting point of134° to 137°C.

Anal. Calcd. for C₁₆ H₂₀ O₂ : C, 78.65; H, 8.25.

Found: C, 78.50; H, 8.17.

EXAMPLE 82B

1'-Hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[40]

A solution of 5 g. (0.019 M) of spiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9](prepared as in Example 16B) in 60 ml. oftetrahydrofuran is added to 67 ml. of 3M methyl magnesium bromide inether. After standing for about 17 hours at room temperature, themixture is cooled in ice and treated cautiously with 50 ml. of saturatedammonium chloride. The organic layer is separated, diluted with benzeneand washed with water and brine. The solution is evaporated to drynessand recrystallized from methylene chloride: cyclohexane to give 3.7 g.(71%) of 1'-hydroxy-1' -methylspiro(cyclohexane- 1,2'-indan)-4-oneethylene ketal [40], melting at 140° to 143°C.

Anal. Calcd for C₁₇ H₂₂ O₃ : C, 74.47; H, 8.08.

Found: C, 74.21; H, 8.09.

Following the procedure of Example 82B but substituting otherspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketals[9] asstarting materials, such as

4'-ethoxyspiro(cyclohexane-1,2'-indan)-1',4-dione ethylene ketal[9],yields,

4'-ethoxy-1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-oneethylene ketal[40].

EXAMPLE 83B

1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-one [41]

A solution of 9.82 g. (0.036 M) of1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[40](prepared as in Example 82B) and 25 ml. of 2.5 N hydrochloric acidin 250 ml. of acetone is stirred at room temperature for about 17 hours.The solvent is then removed under vacuum and the residue dissolved inether and water. The organic layer is washed with water and brine andevaporated to dryness. The residue is recrystallized from petroleumether to give 5.12 g. (67%) of1'-exomethylenespiro(cyclohexane-1,2'-indan)-4-one[41], having a meltingpoint of 60° to 62°C. The NMR spectrum of this compound is in agreementwith its expected structure.

Following the procedure of Example 83B but substituting other1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one ethyleneketals[40] as starting materials, such as

6'-chloro-1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-oneethylene ketal[40], yields,

6'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'indan)-4-one[41].

EXAMPLE 84B

1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42]

A mixture of 2.17 g. (0.010 M) of1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one[41] (prepared as inExample 83B) and 0.75 g. of sodium borohydride in 40 ml. of isopropanolis stirred at room temperature for about 6 hours. The solvent is removedunder vacuum and the residue dissolved in water and ether. The organiclayer is washed with water and brine and evaporated to dryness. Theresidue is chromatographed on a column of 250 ml. of silica gel andeluted with 20% acetone: Skellysolve B. There is obtained 0.08 g. ofsolid, having a melting point of 65° to 69° C. and an NMR spectrum inagreement with the structure of a compound having its hydroxysubstitutent in the axial position, namely,1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-trans-ol[42]. This isfollowed by a gum that crystallizes only in the presence of water,giving 1.71 g. (78% yield) of product melting at 57° to 61° C. and anNMR spectrum in agreement with the structure of a compound having itshydroxy substituent in the equatorial position, namely,1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-cis-ol[42].

Following the procedure of Example 84B but substituting other1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ones [41] as startingmaterials, such as

1. 4'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one[41],

2. 5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one[41],and the like,

yields, respectively,

1. trans and cis4'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42],

2. trans and cis5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42], andthe like.

EXAMPLE 85B

1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [43]

To an ice cold solution of 4.26 g. (0.020 M) of1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42] (prepared as inExample 84β) in 40 ml. of pyridine, 4.3 ml. of methanesulfonyl chlorideis added. After about 7 hours the mixture is poured into ice: water. Thegum that precipitates is extracted with ether and the organic layerwashed successively with water, 2.5 N hydrochloric acid, water andbrine, then evaporated to dryness. The residue is recrystallized from asmall amount of methanol to give 4.82 g. (83%) of1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[43], have a melting point of 72° to 74° C.

Anal. Calcd. for C₁₆ H₂₀ O₃ S: C, 65.72; H, 6.89; M.W. 292.

Found: C, 65.12; H, 7.12; m/e 292.

Following the procedure of Example 85B but substituting other1'-exo-methylenespiro(cyclohexane-1,2'-indan)4-ols[42] as startingmaterials, such as

7'-bromo-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42],

yields,

7'-bromo-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-olmethanesulfonate [43].

EXAMPLE 86B

1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]

A mixture of 5.65 g. (0.019 M) of1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [43](prepared as in Example 85B) and 5.65 g. of sodium azide is heated forabout 17 hours in an oil bath at about 90° C. The solvent is removedunder vacuum and the residue dissolved in benzene and water. The organiclayer is washed with water and brine evaporated to dryness to give1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ylazide[44]. The residue[44] in 80 ml. of tetrahydrofuran is added to 0.75 g. of lithiumaluminum hydride in 10 ml. of tetrahydrofuran. After about 5 hours atroom temperature the mixture is cooled in ice and treated successivelywith 0.75 ml. of water, 0.75 ml. of water, 0.75 ml. of 15% aqueoussodium hydroxide solution and 2.25 ml. of water. The inorganic gel iscollected on a filter and the filtrate evaporated to dryness. An ethersolution of the residue is treated with 6 N hydrogen chloride in ether.The precipitated salt is recrystallized from methylene chloride to give3.08 g. (61%) of 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)], having a melting point of 250° to 253° C.

Anal. Calcd. for C₁₅ H₂₀ ClN.H₂ O: C, 67.29; H, 8.29; N, 5.23.

Found: C, 67.50; H, 7.92; N, 5.21.

Following the procedure of Example 86B but substituting other1'-exo-methylenespiro(cyclohexane-1,2'-indan)4-ol methanesulfonates [43]as starting materials, such as

5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-olmethanesulfonate [I(b)],

yields,

5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-aminehydrochloride [I(b)].

EXAMPLE 87B

1-[1'-Methylenespiro(cyclohexane-1,2'-indan)-4-yl]piperidine [I(b)]

The amine prepared from 1.41 g. (0.0056 M) of1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)], 1,81 g. of 1,5-diiodopentane and 1.55 g. of potassium carbonatein 15 ml. of ethanol is stirred at reflux temperature for about 18hours. The mixture is allowed to cool, diluted with water and the solidcollected on a filter. The solid is recrystallized from methanol to give1.05 g. (67% yield) of1-[1'-methylenespiro(cyclohexane-1,2'-indan)-4-yl]piperidine [I(b)],also named 1'exo-methylenespiro(cyclohexane-1,2'-indan)piperidine,having a melting point of 93° to 95° C.

Anal. Calcd. for C₂₀ H₂₇ N: C, 85,35; H, 9.67; N, 4.90.

Found: C, 85.58; H, 9.99; N, 5.24.

Following the procedure of Example 87B but substituting other1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine acid additionsalts [I(b)]and other dihaloalkanes in stoichiometrically appropriateamounts as starting materials, such as

5'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-aminehydrochloride[I(b)] and 1,6-dibromohexane,

yields,

1-[5'-chloro-1'-methylenespiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimine hydrochloride [I(b)].

EXAMPLE 88B

4'-Fluoro-4-[[1'-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]butyrophenonehydrochloride [I(b)]

A mixture of the free base obtained from 2 g. (0.0080 M) of1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 86B), 1.6 g. of potassium iodide, 2.49 g.of potassium carbonate and 2.32 g. of the 2,2-dimethyl-1,3-propanediolketal of 4-chloro-4'-fluorobutyrophenone in 40 ml. of dimethylformamideis stirred in an oil bath at about 90° C. for about 18 hours. Thesolvent is then removed under vacuum and the residue dissolved inbenzene and water. The organic layer is washed with water and brine andevaporated to dryness. The residue is stirred with 15 ml. of 2.5 Nhydrochloric acid and 30 ml. of methanol for about 3 hours. The methanolis then removed and the solid collected on a filter. This material isrecrystallized from methanol: ethyl acetate to give 0.95 g. (29%) of4'-fluoro-4-[[1'-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]butyrophenonehydrochloride [I(b)], having a melting point of 208° to 211° C.

Anal. Calcd. for C₂₅ H₂₉ ClFNO: C, 72.53; H, 7.06; N, 3.38.

Found: C, 72.20; H, 7.19; N, 3.68.

Following the procedure of Example 88B but substituting acid additionsalts of other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and other ω-haloalkanaryl ketones in stoichiometricallyappropriate amounts, such as

4'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-aminehydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of3-chloro-4'-methylpropiophenone,

yields.

4'-methyl-3-[[4'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]propionphenonehydrochloride [I(b)].

EXAMPLE 89B

Ethyl 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-carbamate [I(b)]

Following the procedure of Example 40B but substituting1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 86B) as starting material, yields,ethyl-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-carbamate [I(b)].

Following the procedure of Example 89B but substituting acid additionsalts of other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and other lower alkyl haloformates, such as

6'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-aminehydrochloride [I(b)] and butyl chloroformate,

yields,

butyl 6'-chloro-1'-exo-methylenespiro(cyclohexane1,2'-indan)-4-carbamate[I(b)].

EXAMPLE 90B

1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride [I(b)]

Following the procedure of Example 43B but substituting ethyl1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-carbamate [I(b)](prepared as in Example 89B) as starting material, yields1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride [I(b)].

Following the procedure of Example 90B but substituting other loweralkyl 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-carbamates [I(b)]as starting materials, such as

butyl 5'-ethoxy-1'-exo-methylenespiro(cyclohexane1,2'-indan)-4-carbamate[I(b)],

yields,

5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride [I(b)], and the like.

EXAMPLE 91B

4'-Fluoro-4-[methyl[1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]butyrophenonehydrochloride [I(b)]

Following the procedure of Example 46B but substituting1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-methyl-aminehydrochloride [I(b)] (prepared as in Example 90B) as starting material,yields4'-fluoro-4-[methyl[1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]butyrophenonehydrochloride [I(b)].

Following the procedure of Example 91B but substituting acid additionsalts of other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-loweralkylamines [I(b)] and the 2,2-dimethyl-1,3-propanediol ketals of otherω-haloalkanaryl ketones in stoichiometrically appropriate amounts, suchas

7'-bromo-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-methylaminehydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of5-chloro-4'-propylvalerophenone,

yields,

4'-propyl-5-[methyl[7'-bromo-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]valerophenonehydrochloride [I(b)].

EXAMPLE 1C

4-Benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal(1)

A solution of 22.3 g. (0.77 M) of4-benzyl-4-carbomethoxy-1-cyclohexaneone ethylene ketal [5] (prepared asin Example 4B) in 220 ml. of tetrahydrofuran is added to 3 g. of lithiumaluminum hydride in 30 ml. of tetrahydrofuran. The mixture is stirred atreflux temperature for about 5.5 hours and then cooled in ice. There isadded successively 3 ml. of water, 3 ml. of aqueous 15% sodium hydroxidesolution and 9 ml. of water. The inorganic gel is collected on a filterand the filtrate evaporated to dryness. The residue is recrystallizedfrom methylene chloride: Skellysolve B to give 18.8 g. (93% yield) of4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal (1), having amelting point of 76° to 78° C.

Anal. Calcd. for C₁₆ H₂₂ O₃ : C, 73.25; H, 8.45.

Found: C, 73.08; H, 8.65.

Following the procedure of Example 1C but substituting other4-benzyl-4-carbomethoxy-1-cyclohexanone ethylene ketals [5] as startingmaterials, such as

1. 4-(p-methylbenzyl)-4-carbomethoxy-1-cyclohexane ethylene ketal [5],

2. 4-(m-methoxybenzyl)-4-carbomethoxy-1-cyclohexane ethylene ketal [5],and the like,

yields respectively,

1. 4-(p-methylbenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal(1),

2. 4-(m-methoxybenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal(1), and the like.

EXAMPLE 2C

4-Benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate(2)

To an ice cold solution of 4-benzyl-4-hydroxymethylcyclohexan-1-oneethylene ketal (1) (prepared in Example 1C) in 100 ml. of pyridine, 19ml. of methanesulfonyl chloride is added. After standing in the cold forabout 5.5 hours, the mixture is poured into ice: water. The gum thatprecipitates is extracted with ether. The organic layer is washedsuccessively with water, ice cold 2.5 N hydrochloric acid, water,saturated aqueous sodium bicarbonate solution and brine, and thenevaporated to dryness. The residual solid is recrystallized frommethylene chloride: Skellysolve B to give 21.1 g. (86%) of4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate(2).

Following the procedure of Example 2C but substituting other4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketals (1) as startingmaterials, such as

1. 4-(p-ethoxybenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal(1),

2. 4-(m-propionylamidobenzyl)-4-hydroxymethylcyclohexan-1-ethylene ketal(1), and the like,

yields, respectively,

1. 4-(p-ethoxybenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketalmethanesulfonate (2),

2. 4-(m-propionylamidobenzyl)-4-hydroxymethylcyclohexan-1-one ethyleneketal methanesulfonate (2), and the like.

EXAMPLE 3C

4-Benzylcyclohexan-4-acetic acid-1-one ethylene ketal (4)

1. A mixture of 18.6 g. (0.055 M) of4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate(2) (prepared as in Example 2C) and 18 g. of potassium cyanide in 180ml. of hexamethylphosphoramide is heated for about 17 hours in an oilbath at about 145° C. The resulting gel is allowed to cool, diluted to800 ml. with water and extracted with benzene. The organic layer iswashed with water and brine and evaporated to dryness. The residue ischromatographed on 1 l. of silica gel and eluted with 25% ethyl acetatein Skellysolve B and the fractions found similar to TLC pooled to give4-benzyl-4-cyanocyclohexan-1-one ethylene ketal (3).

2. The product (3), obtained in part (1), above, is heated with 14.5 g.of potassium hydroxide in 105 ml. of ethylene glycol for about 17 hours.The mixture is then allowed to cool, diluted with water and washed oncewith ether. The aqueous layer is then covered with ether and cautiouslyacidified. The organic layer separated, washed with brine and evaporatedto dryness. The residue is recrystallized from cyclohexane to give 12.3g. (77%) of 4-benzylcyclohexan-4-acetic acid-1-one ethylene ketal (4),melting at 116° to 118° C. The analytical sample has a melting point of118° to 120° C.

Anal. Calcd. for C₁₇ H₂₂ O₄ : C, 70.32; H, 7.64.

Found: C, 70.50; H, 7.83.

Following the procedure of Example 3C but substituting other4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketals (2) as startingmaterials, such as

1. 4-(o-aminobenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketalmethanesulfonate (2),

2. 4-(m-fluorobenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketalmethanesulfonate (2), and the like,

yields, respectively,

1. 4-(o-aminobenzyl)cyclohexan-4-acetic acid-1-one ethylene ketal (4),

2. 4-(m-fluorobenzyl)cyclohexan-4-acetic acid-1-one ethylene ketal (4),and the like.

EXAMPLE 4C

4-Benzylcyclohexan-4-acetic acid-1-one (5)

A solution of 12.3 g. of 4-benzylcyclohexan-4-acetic acid-1-one ethyleneketal (4) (prepared in Example 3C) and 18 ml. of 2.5 N hydrochloric acidin 180 ml. of acetone is stirred at room temperature for about 62 hours.Most of the solvent is removed under vacuum and the residue dissolved inether and water. The organic layer is washed with water and brine andevaporated to dryness. The residue is recrystallized from ether:Skellysolve B to give 7.94 g. (76%) of 4-benzylcyclohexan-4-aceticacid-1-one (5), having a melting point of 85° to 87° C. The analyticalsample has a melting point of 91° to 92° C.

Anal. Calcd. for C₁₅ H₁₈ O₃ : C, 73.15; H, 7.37.

Found: C, 73.01; H, 7.58.

Following the procedure of Example 4C but substituting other4-benzylcyclohexan-4-acetic acid-1-one ethylene ketals (4) as startingmaterials, such as

1. 4-(p-ethoxybenzyl)cyclohexan-4-acetic acid-1-one ethylene ketal (4),

2. 4-(m-nitrobenzyl)cyclohexan-4-acetic acid-1-one ethylene ketal (4),and the like,

yields, respectively,

1. 4-(p-ethoxybenzyl)cyclohexan-4-acetic acid-1-one (5),

2. 4-(m-nitrobenzyl)cyclohexan-4-acetic acid-1-one (5),

and the like.

EXAMPLE 5C

3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione (6)

A solution of 6.43 g. (0.026 M) of 4-benzylcyclohexan-4-aceticacid-1-one (5) (prepared as in Example 4C) in 40 ml. of freshlydistilled hydrogen fluoride is allowed to evaporate at room temperaturefor about 62 hours. The residue is dissolved in methylene chloride andthis solution is washed successively with aqueous sodium bicarbonatesolution, water and brine. The solution is evaporated to dryness andchromatographed on a colulmn of 650 ml. of silica gel and eluted with20% acetone: Skellysolve B. The crystalline fractions are combined andrecrystallized from 20% acetone: Skellysolve B to give 1.95 g. (33%) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene-4',4-dione (6),having a melting point of 158° to 160° C.

Anal. Calcd. for C₁₅ H₁₆ O: C, 78.92; H, 7.06; M.W. 228.

Found: C, 78.69; H, 7.31; m/e 228.

Following the procedure of Example 5C but substituting other4-benzylcyclohexan-4-acetic acid-1-ones (5) as starting materials, suchas

1. 4-(6'-methylaminobenzyl)cyclohexan-4-acetic acid-1-one (5),

2. 4-(7'-chlorobenzyl)cyclohexan-4-acetic acid-1-one (5), and the like,

yields, respectively,

1.3',4'-dihydro[6'-methylaminospiro[cyclohexane-1,2'(1'H)-naphthalene]-1',4-dione(6),

2.3',4'-dihydro[7'-chlorospiro[cyclohexane-1,2'-(1'H)-naphthalene]-1',4-dione(6), and the like.

EXAMPLE 6C

3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione,4-(ethylene ketal) (7)

A mixture of 2.65 g. (0.012 M) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione (6)(prepared as in Example 5C), 0.72 g. (0.65 ml.) of ethylene glycol and0.20 g. of p-toluenesulfonic acid in 100 ml. of benzene is heated atreflux under a Dean-Stark trap for about 14 hours. The mixture isallowed to cool, washed with aqueous sodium bicarbonate solution andbrine and evaporated to dryness. The residue is chromatographed on a 300ml. column of silica gel and eluted with 25% ethyl acetate: SkellysolveB to give 2.2 g. (70%) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]4',4-dione,ethylene ketal (7), melting at 90° to 91.5° C.

Anal. Calcd. for C₁₇ H₂₀ O₃ : C, 74.97; H, 7.40.

Found: C, 75.00; H, 7.66.

Following the procedure of Example 6C but substituting other3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-diones (6) asstarting materials, such as

1.3',4'-dihydro[5'-propoxyspiro[cyclohexane-1,2'(1'H)-naphthalene]-1',4-dione(6),

2.3',4'-dihydro[6'-ethylspiro[cyclohexane-1,2'-(1'H)-naphthalene]-4',4-dione(6), and the like,

yields, respective

1.3',4'-dihydro[5'-propoxyspiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione,4-(ethylene ketal) (7),

2.3',4'-dihydro[6'-ethylspiro[cyclohexane-1,2'-(1'H)-naphthalene]-4',4-dione,4-(ethylene ketal) (7), and the like.

EXAMPLE 7C

3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethyleneketal (8)

A mixture of 2.2 g. (0.0081 M) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione,4-(ethylene ketal) (7) (prepared in Example 7C), 1.2 ml. of hydrazinehydrate and 1.6 g. of potassium hydroxide, is heated at reflux for about1 hour. Solvent is removed by distillation to bring the temperature ofthe reaction mixture to about 200° C., and the refluxing is continuedfor about 17 hours, The mixture is then poured into water and extractedwith ether. The organic layer is washed with water and brine andevaporated to dryness. The residue is recrystallized from petroleumether to give 1.86 g. (88%) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen] 4-one, ethyleneketal (8), having having a melting point of 79° to 81° C.

Anal. Calcd. for C₁₇ H₂₂ O₂ : C, 79.03; H, 8.59.

Found: C, 79.14; H, 8.72.

Following the procedure of Example 7C but substituting other3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione,4-(ethylene ketals) (7) as starting materials, such as

3',4'-dihydro[7'-nitrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione,4-(2,2-dimethyltrimethylene ketal) (7)

yields,

3',4'-dihydro[7'-nitrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-one,ethylene ketal (8).

EXAMPLE 8C

3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10)

1. A mixture of 1.86 g. (0.0072 mole) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethyleneketal (8) (prepared in Example 7C) and 2 ml. of 2.5 N hydrochloric acidin 40 ml. of acetone is heated at reflux for about 17 hours. Most of thesolvent is removed under vacuum and the residue dissolved in water andether. The organic layer is washed with water and brine and thenevaporated to dryness to give3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one (9).

2. The residue (9), obtained in part (1), above, is dissolved in 50 ml.of 95% isopropanol and treated with 1 g. of sodium borohydride. Afterabout 5 hours the solvent is removed under vacuum and the residuedissolved in water and ether. The organic layer is washed with water andbrine, evaporated to dryness, the crude produce chromatographed on a 170ml. column of silica gel and eluted with methylene chloride. There isfirst obtained 0.24 g. of starting material (8). The product fractionsare combined and recrystallized from Skellysolve B to give 0.65 g. (42%)of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10),melting at 78° to 82° C.

Anal. Calcd. for C₁₅ H₂₀ O: C, 82.28; H, 9.32. M.W. 216.

Found: C, 83.37; H, 9.43, m/e 216.

Following the procedure of Example 8C but substituting other3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethyleneketals (8) as starting materials, such as

3',4'-dihydro[6'-fluorospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one,2,2-dimethyltriethylene ketal (8), yields,

3',4'-dihydro[6'-fluorospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol(10).

EXAMPLE 9C

3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-olmethanesulfonate (11)

To an ice cold solution of 2.16 g. (0.01 M) of 3',,4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10) (preparedas in Example 8C) in 10 ml. of pyridine, 2 ml. of methanesulfonylchloride is added. After about 4 hours in the cold, the mixture ispoured onto ice: water. The resulting solid precipitate is collected ona filter and recrystallized from ether: petroleum ether to give 2.52 g.(86%) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-olmethansulfonate (11), melting at 66° to 69° C.

Anal. Calcd. for C₁₆ H₂₂ O₃ S: C, 65.27; H, 7.53

Found: C, 65.38; H, 7.54.

Following the procedure of Example 9C but substituting other3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ols (10) andother lower alkyl sulfonyl halides as starting materials, such as

3',4'-dihydro[5'-ethoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10)and propane sulfonyl bromide, yields,

3',4'-dihydro[5'-ethoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-olpropanesulfonate (11).

EXAMPLE 10C

3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylaminehydrochloride [I(c)]

A mixture of 2.52 g. (0.0085 M) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-olmethanesulfonate (11) (prepared in Example 9C) and 2.5 g. of sodiumazide in 25 ml. of dimethylformamide is heated for about 17 hours in anoil bath at about 90° C. The solvent is then removed under vacuum andthe residue,3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-napthalen]-4-ylazide, dissolvedin benzene and water. The organic layer is washed with water and brineand evaporated to dryness. A solution of the residue in 60 ml. oftetrahydrofuran is added to 0.35 g. of lithium aluminum hydride in 10ml. of tetrahydrofuran. After stirring for about 4 hours at roomtemperature, the mixture is cooled in ice and treated successively with0.35 ml. of water, 0.35 ml. of aqueous 15% sodium hydroxide solution and1.05 ml. of water. The resulting inorganic gel is collected on a filterand the filtrate evaporated to dryness. A solution of the residue inether is treated with 6 N hydrogen chloride in ether. The resultingsolid is recrystallized from methylene chloride: ethyl acetate to give1.65 g. (77%) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylaminehydrochloride [I(c)], melting at 208° to 211° C.

Following the procedure of Example 10C but substituting other3',4'-dihydrospiro[cyclohexane-1,2'(1'-H)-naphthalen]-4-ol loweralkylsulfonates (11) as starting materials, such as

3',4'-dihydro[6'-fluorospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-olpropanesulfonate (11), yields,

3',4'-dihydro[6'-fluorospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylaminehydrochloride [I(c)].

EXAMPLE 11C

1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine[I(c)]

The amine prepared from 1.5 g. of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylaminehydrochloride [I(c)] (prepared as in Example 10C), 1.9 g. of1,5-diiodopentane and 1.6 g. of potassium carbonate in 18 ml. of ethanolis stirred at reflux temperature for about 18 hours. The mixture aftercooling is diluted with water, the solid collected on a filter andrecrystallized from methanol to give1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine[I(c)].

Following the procedure of Example 11C but substituting acid additionsalts of the same and other3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamines [I(c)]and other dihaloalkanes, such as

1. 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)]and 1,4-diiodobutane,

2. 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)]and 1,6-diiodohexane,

3. 5'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] and1,5-diiodopentane and the like,

yields respectively,

1. 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylpyrrolidine [I(c)],

2. 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylhexamethyleneimine [I(c)],

3. 1-[5'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl piperidine[I(c)], and the like.

EXAMPLE 12C

4'-Fluoro-4-[[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]amino]butyrophenonehydrochloride [I(c)]

The free base from 1.65 g. (0.0066 M) of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylaminehydrochloride [I(c)] (prepared in Example 10C), 1.34 g. of potassiumiodide, 2.06 g. of potassium carbonate and 1.9 g. of the2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in35 ml. of dimethylformamide are heated in an oil bath at about 90° C.for about 18 hours. The solvent is removed under vacuum and the residuethat remains in dissolved in benzene and water. The organic layer iswashed with water and brine and evaporated to dryness. A mixture of theresidue and 10 ml. of 2.5 N hydrochloric acid in 20 ml. of methanol isstirred at room temperature for about 4 hours. The methanol is thenremoved under vacuum and the solid collected on a filter. This materialis recrystallized twice from methylene chloride: ethyl acetate to give1.07 g. (39% yield) of4'-fluoro-4-[[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]amino]butyrophenonehydrochloride [I(c), having a melting point of 182° to 184° C.

Anal. Calcd for C₂₅ H₃₁ ClFNO: C, 72.18; H, 7.51; N, 3.37; M.W. 379.

Found: C, 72.20; H, 7.53; N, 3.47; m/e 379.

Following the procedure of Example 12C but substituting another3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] asstarting material and the 2,2-dimethyl-1,3-propanediol ketal of anotherω-haloalkanaryl ketone, such as

5'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride[I(c)] and the 2,2-dimethyl-1,3-propanediol ketal of4'-bromo-4-chlorobutyrophenone,

yields,

4'-bromo-4-[[5'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]amino]butyrophenonehydrochloride [I(c)].

EXAMPLE 13C

Ethyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate[I(c)]

To an ice cooled solution of the free base prepared from 1.5 g. of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylaminehydrochloride [I(c)] (prepared as in Example 10C) in 12 ml. of pyridine,1 ml. of ethyl chloroformate is added. The mixture is allowed to standin the cold for about 5 hours and then poured into ice water. The solidthat precipitates is collected on a filter and recrystallized frommethylene chloride: benzene to give ethyl3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate[I(c)].

Following the procedure of Example 13C but substituting another3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] asstarting material and another lower alkyl haloformate, such as

5'-ethoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] andpropyl bromoformate, and the like,

yields,

propyl 5'-ethoxyspiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate[I(c)].

EXAMPLE 14C

3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylaminehydrochloride [I(c)]

To a suspension of 0.22 g. of lithium aluminum hydride in 10 ml. oftetrahydrofuran, a tetrahydrofuran solution of 1.3 g. of ethyl3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate [I(c)](prepared as in Example 13C) is added. The mixture is stirred at refluxtemperature for about 6 hours, at room temperature for about 18 hours,and cooled in an ice bath. To this is added successively, 0.22 ml. ofwater, 0.22 ml. of 15% aqueous sodium hydroxide solution and 0.66 ml. ofwater. The resulting inorganic gel is collected on a filter, rinsed withether and the filtrates evaporated to dryness. The residue is dissolvedin a small amount of ether and treated with an excess of 6.4 N hydrogenchloride in ether. The resulting precipitate is collected on a filterand recrystallized from methanol: ethyl acetate to give3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methyl-amine hydrochloride [I(c)].

Following the procedure of Example 14C but substituting another loweralkyl 3',4'-dihydrospiro[cyclohexane-1,2'-(1'H)-naphthalene]-4-carbamate[I(c)] as starting material, such as

ethyl 5'-isopropylspiro[cyclohexane-1,2'(1'H)-naphthalen3]-4-carbamate[I(c)], yields,

5'-isopropylspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylaminehydrochloride [I(c)].

EXAMPLE 15C

4'-Fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino]-butyrophenonehydrochloride [I(c)]

A mixture of the free base prepared from 0.81 g. of3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylaminehydrochloride [I(c)] (obtained as in Example 14C), 0.63 g. of potassiumiodide, 0.96 g. of potassium carbonate and 0.87 g. of the2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in15 ml. of dimethylformamide is heated together in an oil bath at about90° C. for about 20 hours. The solvent is removed under vacuum and theresidue dissolved in water and benzene. The organic layer is washed withwater and brine and evaporated to dryness. A mixture of the residue, 6ml. of 2.5 N hydrochloric acid and 12 ml. of methanol is stirred at roomtemperature for about 1.5 hours and most of the methanol removed undervacuum. The residual suspended solid is collected on a filter, washedwith ether and recrystallized from methanol: ethyl acetate to give4'-fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino]butyrophenonehydrochloride [I(c)].

Following the procedure of Example 15C but substituting another3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-loweralkylamine [I(c)] as starting material and the2,2-dimethyl-1,3-propanediol ketal of another ω-haloalkanaryl ketone,such as

1. 6'-bromospiro(cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamine[I(c)] and the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-4'-methoxybutyrophenone,

2. 5'-propoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-ethylamine[I(c)] and the 2,2-dimethyl-1,3-propanediol ketal of4-chloro-2'-ethylbutyrophenone, and the like.

yields, respectively,

1.4'-methoxy-4-[6'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino]butyrophenonehydrochloride [I(c)],

2.2'-ethyl-4-[5'-propoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-ethylamino]butyrophenonehydrochloride [I(c)], and the like.

I claim:
 1. A compound of the formula ##SPC23## wherein the sum of A andB carbon atoms is at least the integer 2; A is --(CH₂)_(n) ⁻ wherein nis 1 through 5; B is absent or --(CH₂)_(n) ⁻ wherein n is 1 through 3;R¹ is selected from the group consisting of hydrogen and lower alkyl of1 through 3 carbon atoms; R² is selected from the group consisting ofhydrogen, lower alkyl of 1 through 3 carbon atoms, R¹ and R² takentogether with --N< is a saturated heterocyclic amino radical selectedfrom the group consisting of pyrrolidino, piperidino, andhexamethylenimino; Z is selected from the group consisting of hydrogen,lower alkyl of 1 through 3 carbon atoms, lower alkoxy of 1 through 3carbon atoms, nitro, amino, monoalkylamino of 1 through 3 carbon atoms,alkanoylamido of 1 through 4 carbon atoms, bromine, chlorine andfluorine; and a pharmacologically acceptable acid addition salt thereof.2. A compound of claim 1 wherein A is --(CH₂)_(N) ⁻ wherein n is 3, B isabsent, R¹, R² and Z are hydrogen and the pharmacologically acceptableacid addition salt is that of hydrochloric acid, namely,3',4'-dihydrospiro(cyclohexane-1,1'-(2'H)-naphthalen)-4-ylaminehydrochloride.
 3. A compound of claim 1 wherein A is --(CH₂)_(n) ⁻wherein n is 3, B is absent, R¹ is methyl, R² and Z are hydrogen and thepharmacologically acceptable acid addition salt is that of hydrochloricacid, namely,3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl-N-methylaminehydrochloride.
 4. A compound of claim 1 wherein A and B are --(CH₂)_(n)⁻ wherein n is 1, R¹, R² and Z are hydrogen and the pharmacologicallyacceptable acid addition salt is that of hydrochloric acid, namely,spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride.
 5. A compound ofclaim 1 wherein A and B are --(CH₂)_(n) ⁻ wherein n is 1, R¹ is methyl,R² and Z are hydrogen and the pharmacologically acceptable acid additionsalt is that of hydrochloric acid, namely,spiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride.
 6. A compoundof claim 1 wherein A and B are --(CH₂)_(n) ⁻ wherein n is 1, R¹ ismethyl, R² is hydrogen, Z is 5'-methyl and the pharmacologicallyacceptable acid addition salt is that of hydrochloric acid, namely,5'-methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride.
 7. Acompound of claim 1 wherein A and B are --(CH₂ (_(n) ⁻ wherein n is 1,R¹ and R² are hydrogen, Z is 5'-methoxy and the pharmacologicallyacceptable acid addition salt is that of hydrochloric acid, namely,5'-methoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride.
 8. Acompound of claim 1 wherein A and B are --(CH₂)_(n) ⁻ wherein n is 1, R¹and R² are hydrogen, Z is 5'-acetamido and the pharmacologicallyacceptable acid addition salt is that of hydrochloric acid, namely,N-[4-aminospiro[cyclohexane-1,2'-indan]-5'-yl]acetamide hydrochloride.9. A compound of claim 1 wherein A and B are --(CH₂)_(n) ⁻ wherein for An is 2 and for B n is 1, R¹, R² and Z are hydrogen and thepharmacologically acceptable acid addition salt is that of hydrochloricacid, namely,3',4'-dihydrospiro(cyclohexane-1,2'(1'H)-naphthalen)-4-ylaminehydrochloride.
 10. A compound of claim 1 wherein A and B are --(CH₂)_(n)⁻ wherein n is 1, R¹ and R² taken together with --N< is piperidino, Z ishydrogen and the pharmacologically acceptable acid addition salt is thatof hydrochloric acid, namely,1-[spiro(cyclohexane-1,2'-indane)-4-yl]-piperidine hydrochloride.